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WO2018191628A1 - Multi-drug therapies for tuberculosis treatment - Google Patents

Multi-drug therapies for tuberculosis treatment Download PDF

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Publication number
WO2018191628A1
WO2018191628A1 PCT/US2018/027505 US2018027505W WO2018191628A1 WO 2018191628 A1 WO2018191628 A1 WO 2018191628A1 US 2018027505 W US2018027505 W US 2018027505W WO 2018191628 A1 WO2018191628 A1 WO 2018191628A1
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WO
WIPO (PCT)
Prior art keywords
opc
rifampicin
clofazimine
pyrazinamide
ethambutol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2018/027505
Other languages
French (fr)
Inventor
Chih-Ming Ho
Marcus Aaron HORWITZ
Aleidy Marlene Silva VITE
Xianting DING
Daniel L. Clemens
Bai-Yu Lee Clemens
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
Original Assignee
University of California Berkeley
University of California San Diego UCSD
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Publication date
Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2018191628A1 publication Critical patent/WO2018191628A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109.
  • a composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination selected from the group of drug combinations 1-176 tabulated in Table 1.
  • Mycobacterium tuberculosis Mycobacterium bovis, Mycobacterium africanum,
  • Mycobacterium canetti or Mycobacterium microti, in a cell infected therewith, comprising, or alternatively consisting essentially of, or yet consisting of, contacting the cell with an effective amount of a pharmaceutical composition described herein.
  • TB tuberculosis
  • a method of treating tuberculosis (TB) in a subject in need thereof comprising, or alternatively consisting essentially of, or yet consisting of, administering to the subject an effective amount of a pharmaceutical composition described herein.
  • compositions as described herein for use in the treatment of tuberculosis (TB) in a subject in need thereof.
  • PRS Parabolic Response Surface
  • TB tuberculosis
  • patient demographic e.g., child, adult, pregnant, HIV-positive, and so forth.
  • the two main classifications of TB treatment are "first-line” and "second-line”.
  • First-line treatment of drug-sensitive TB is a 4-drug regimen: isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB).
  • IH isoniazid
  • RAF rifampin
  • PZA pyrazinamide
  • EMB ethambutol
  • Second-line treatments used to treat drug-resistant TB utilize 3-5 other drugs in combination:
  • FDCs used for TB treatment include Rifater [isoniazid (INH), pyrazinamide (PZA), and rifampicin (RIF)] and Rifamate [isoniazid (INH) and rifampin (RIF)].
  • MDR-TB Multi-drug resistant TB
  • MDR-TB is a categorization of strains of TB that are resistant to at least both isoniazid and rifampicin. MDR-TB arises from inappropriate treatment such as: use of poor quality medicines, administration of improper treatment regimens, and failing to ensure the patient has completed the whole course of treatment. Because MDR-TB is due to bacteria resistant to the two most powerful first-line anti-TB drugs, MDR-TB patients are then treated with first- line drugs to which the strain is sensitive plus several second-line drugs.
  • XDR-TB Extensively drug-resistant TB
  • MDR-TB is specified as MDR-TB that is additionally resistant to several other classes of anti-TB drugs including the most effective second-line anti-TB drugs. It is estimated that about 9.6% of reported MDR-TB cases are XDR-TB.
  • Embodiments of this disclosure are directed to a combination of drugs in respective doses, uses thereof and methods therewith for treating TB, and a method for determining the optimum drug doses in the combination.
  • the method for determining the optimum drug doses in the combination involves three stages. First, the optimal drug-dose combinations are determined on the basis of in vitro studies on the efficacy of various drug-dose combinations in inhibiting and in killing Mycobacterium tuberculosis, using a Parabolic Response Surface (PRS) [formerly Feedback System Control (FSC)] optimization scheme.
  • PRS Parabolic Response Surface
  • FSC Feedback System Control
  • the terms “substantially” and “about” are used to describe and account for small variations.
  • the terms can refer to instances in which the event or circumstance occurs precisely as well as instances in which the event or circumstance occurs to a close approximation.
  • the terms can refer to a range of variation of less than or equal to ⁇ 10% of that numerical value, such as less than or equal to ⁇ 5%, less than or equal to ⁇ 4%, less than or equal to ⁇ 3%, less than or equal to ⁇ 2%, less than or equal to ⁇ 1%), less than or equal to ⁇ 0.5%, less than or equal to ⁇ 0.1%, or less than or equal to ⁇ 0.05%.
  • a range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual values such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth.
  • clofazimine corresponds to N,5-bis(4- chlorophenyl)-3-(propan-2-ylimino)-3,5-dihydrophenazin-2-amine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • ethambutol corresponds to (2,S',2' ) S)-2,2'-(ethane- l,2-diyldiimino)dibutan-l-ol, and is represented by the following structure, or a
  • pretomanid corresponds to (6,S)-2-nitro-6- ⁇ [4- (trifluoromethoxy)benzyl]oxy ⁇ -6,7-dihydro-5H-imidazo[2,l- ⁇ ][l,3]oxazine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • pyrazinamide corresponds to pyrazine-2- carboxamide, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • rifampin is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • SQ109 corresponds to N-adamantan ⁇ -yl-N'- ⁇ ⁇ -S,?- dimethyl-octa-2,6-dienyl)-ethane-l,2-diamine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • bedaquiline corresponds to (li?,2,S)-l-(6-bromo-2- methoxy-3-quinolyl)-4-dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • amoxicillin corresponds to (2S,5R, 6R)-6- ⁇ [(2R)-2-amino- 2-(4-hydroxyphenyl)-acetyl]amino ⁇ -3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane- 24-carboxylic acid, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • clavulanic acid corresponds to (2R,5R,Z)-3-(2- hydroxyethylidene)-7-oxo-4-oxa-l-aza-bicyclo[3.2.0]heptane-2-carboxylic acid, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • delamanid corresponds to (2R)-2- methyl-6-nitro-2-[(4- ⁇ 4-[4-(trifluoromethoxy)phenoxy]-l-piperidinyl ⁇ phenoxy)methyl]-2,3- dihydroimidazo[2, l-6][l,3]oxazole, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
  • linear corresponds to (,S)-N-( ⁇ 3-[3-fluoro-4-(morpholin-4- yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl ⁇ methyl)acetamide and is represented by the following structure or a pharmaceutically acceptable salt thereof:
  • Tautomers refer to isomeric forms of a compound that are in equilibrium with each other.
  • concentrations of the isomeric forms will depend on an environment in which the compound is found and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
  • Stereoisomers of compounds also referred to as “optical isomers,” include all chiral, diastereomeric, and racemic forms of a chemical structure, unless the specific stereochemistry is expressly indicated.
  • compounds used in some embodiments include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions.
  • racemic and diastereomeric mixtures, as well as individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of this disclosure.
  • pharmaceutically acceptable refers to a material that is not
  • the material may be incorporated into a pharmaceutical composition administered to a patient without causing undesirable biological effects or interacting in a deleterious manner with any of other components of the
  • composition in which it is contained is contained.
  • pharmaceutically acceptable is used to refer to a pharmaceutical carrier or excipient, the carrier or excipient is one that has met standards of toxicological and manufacturing testing or that is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • extrapolation technique refers to extrapolation types including, but not limited to linear extrapolation, polynomial, conic section or French curve extrapolation.
  • Pharmacokinetic data for drugs disclosed herein includes data comprising serum levels, tissue levels, metabolism, binding affinities, and bioavailability. Pharmacokinetic data may be acquired through analytical techniques including but not limited to immunoassay, mass spectrometry, MR spectroscopy, spectrophotometry, chromatography, diode array detection, capillary electrophoresis, enzyme linked immunosorbent assay, or
  • Macrophage refers to a type of phagocytotic white blood cell of the immune system. Such machines can perceive their environment and take actions based on what is perceived.
  • AI Artificial Intelligence
  • Machines with AI may display treats such as learning and memory.
  • an "effective amount” is an amount sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations or applications. Such delivery is dependent on a number of variables including the time period for which the individual composition is to be used, the bioavailability of the therapeutic agents included with the composition, the route of administration, etc. It is understood, however, that specific dose levels of the additional therapeutic agents disclosed herein for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal/subject and its body weight, general health, sex, the diet of the animal/subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration.
  • terapéuticaally effective amount or “pharmaceutically effective amount” is an amount sufficient to treat a specified disorder or disease or alternatively to obtain a pharmacological response such as immunosuppression, osteogenesis, bone resorption or mineralization.
  • patient refers to any animal for which treatment is desirable. Patients may be mammals, and typically, as used herein, a patient is a human individual. "Patient” and “subject” are to be understood to be interchangeable.
  • TB inhibition refers to a percentage determined via an inhibition assay, also referred to herein as a “treatment test” described in the working examples which quantifies bacteria via fluorescence or alternatively, by the quantification or colony forming unites (CFUs) as described in the working examples.
  • Administration or treatment in “combination” refers to administering two agents such that their pharmacological and/or therapeutic effects are manifest at the same time. Combination does not require administration at the same time or substantially the same time, although combination can include such administrations. Combination can include sequential administration.
  • Replication refers to the division of bacterial cells or the replication, copying, or transcription of their genetic material including deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and the like.
  • DNA deoxyribonucleic acid
  • RNA ribonucleic acid
  • Contacting refers to introduction of a drug, agent, or
  • treating or “treatment” of a disease in a subject refers to (1) preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease or the symptoms of the disease.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease or trauma), stabilized (i.e., not worsening) state of a condition (including disease or trauma), delay or slowing of condition (including disease or trauma), progression, amelioration or palliation of the condition (including disease or trauma), states and remission (whether partial or total), whether detectable or undetectable.
  • inhibitors refer to attenuating, halting, reversing or attenuating the acceleration of that to which they refer. As used herein these terms may refer to attenuating, halting, reversing or attenuating the acceleration of bacterial replication or killing the bacteria.
  • administering intends local or systemic administration.
  • administration is systemic via, intracerebroventricular, intrathecal, topical, intravenous, intranasal, subcutaneous, intramuscular, or transdermal administration.
  • Local administration is surgical implantation of the compositions described herein.
  • Administration may be accomplished implanting the pharmaceutical composition directly or coating or impregnating a surgical implant or prosthesis with the pharmaceutical
  • compositions of the disclosure may be implanted anywhere throughout the body
  • Drug drugs
  • drugs and the like or “compound,” “compounds” and the like, as used herein, refers to a substance administered to a subject. Drugs of this disclosure are tabulated in Table 1 and described herein. A combination of two substances may together be referred to as a single "drug,” for example the combination of amoxicillin/clavulanic acid (A/C), is a "drug.”
  • A/C amoxicillin/clavulanic acid
  • drug-dose combination refers to a data set including a drug combination and a dose for each respective drug of the drug combination.
  • the doses for each drug in a drug dose-combination can be determined by methods described herein, for example PRS optimization scheme, in vitro, or in vivo testing.
  • a drug dose combination can be expressed in terms of a specific mass or concentration in a solution for each drug.
  • the drug dose combination can be expressed as a ratio of the drugs of a combination.
  • Various drug dose combinations are tabulated in Table 4 herein.
  • Drug combination refers to a combination of three or more drugs which together comprise the "pharmaceutical composition" of the disclosure.
  • Each row 1-176 of Table 1 discloses a "drug combination.”
  • the first row of Table 1 discloses the drug combination: ethambutol, PA824, rifampicin and OPC.
  • a " pharmaceutical composition” typically intends a combination of the active agent(s), e.g., drug(s), and a naturally-occurring or non-naturally-occurring carrier, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers.
  • active agent(s) e.g., drug(s)
  • a naturally-occurring or non-naturally-occurring carrier for example, a detectable agent or label
  • active such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers.
  • Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-oligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume.
  • Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody
  • components which can also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like.
  • Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D- mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.
  • monosaccharides such as fructose, maltose, galactose, glucose, D- mannose, sorbose, and the like
  • disaccharides such as lactose, sucrose
  • salts or zwitterionic forms of compounds of some embodiments which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic-response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
  • the salts can be prepared during a final isolation and purification of the compounds or separately by reacting an appropriate compound in the form of a free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, di gluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phen
  • basic groups in the compounds of some embodiments can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, this disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds of some embodiments and the like.
  • solvates include hydrates formed when a compound of some embodiments contains one or more bound water molecules.
  • Some embodiments of this disclosure include various combinations of known drugs.
  • the combinations show improved efficacy against TB compared with conventional treatments.
  • multiple optimal drug-dose combinations are determined on the basis of in vitro studies and PRS analysis.
  • Certain embodiments of drug combinations have been evaluated on the basis of in vitro TB treatment tests, and achieve > 60% projected TB inhibition.
  • a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109.
  • the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and OPC. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and A/C. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and SQ109.
  • a drug combination is selected from one of the following drug combinations of Table 1, 1-176:
  • the pharmaceutical composition comprises, consists essentially of, or yet consists of one or more carriers.
  • the drugs are combined into a single solid dose formulation.
  • the drugs are present in the same ratio as they are in each drug-dose combination of Table 4.
  • the pharmaceutical composition comprises, consists essentially of, or yet consists a drug dose combination corresponding to a row of Table 4.
  • the drugs are in solution at a concentration according to Table 4.
  • the drugs in the pharmaceutical composition are present in a ratio of their concentrations in Table 4 relative to each other.
  • the drug combinations provide at least one of a number of benefits, including one or more of the following.
  • the drug combinations are treatment combinations that can have higher efficacy than other drug combinations used for TB treatment.
  • the drug combinations provide alternative combinations for the treatment of drug-resistant TB, and also allow faster treatment of drug-resistant TB. Since many of the drug combinations do not include INH and RTF, alternative regimens can be developed that are suitable for the treatment of many cases of MDR-TB. Surprisingly, even though many of the drug combinations do not include the two most powerful first-line anti-TB drugs, INH and RTF, those combinations are shown to be superior to the standard regimen.
  • the regimens do not include, or can omit, fluoroquinolones or aminoglycosides
  • the regimens also can be useful for treatment of many cases of XDR-TB.
  • current drug treatment regimen generally requires 6-8 months of treatment. Treatment of drug-resistant strains takes even longer, typically 24 months. Because treatment is so prolonged, patient compliance is often poor. Poor patient compliance increases the likelihood of drug resistance developing.
  • the proposed drug-dose combinations of this disclosure allow more rapid and more efficacious treatment of both drug-sensitive and drug-resistant TB and greater patient compliance.
  • a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109; for use in the treatment of TB in a subject in need thereof.
  • the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and OPC. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and A/C. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and SQ109.
  • the pharmaceutical composition comprises, consists essentially of, or yet further consists of a drug combination that has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition.
  • treatment comprises, consists essentially of, or yet further consists of administering two or more drugs of the drug combination sequentially. In some embodiments, treatment comprises, consists essentially of, or yet further consists of administering two or more drugs of the drug combination concurrently.
  • the subject is a mammal, including, for example, farm animals, sheep, pigs, cows, horses, pets, dogs, cats; laboratory animals, rats, mice and rabbits.
  • the mammal is a bovine, a feline, a canine, a murine, an equine, or a human .
  • the mammal is a human.
  • TB that is treated is caused by Mycobacterium
  • tuberculosis In other embodiments, the tuberculosis treated is caused by other species in the Mycobacterium tuberculosis complex. In some embodiments, the tuberculosis (TB) is caused by Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, or
  • TB is drug-sensitive TB or MDR-TB or XDR-TB. In some embodiments the TB is active TB. In some embodiments the TB is miliary TB. In some embodiments, the TB is pulmonary TB. In some embodiments the TB is latent TB.
  • the drugs are each independently administered once a day, twice a day or three times a day. In some embodiments, each drug's administration is independently continued for 2 or 4 or 6 or 8 weeks or more, or one, two, three, four or five months or more, or any value therein between. In some embodiments each drug's administration is independently continued for less than 6 months, or less than 9, 12, 15, 18, 21 or 24 months.
  • Some embodiments of this disclosure include methods of treating TB in a patient or other subject in need thereof, comprising, or alternatively consisting essentially of, or yet further consisting of, administering to the patient a pharmaceutically effective amount of a pharmaceutical composition or drug combination described herein.
  • the drug combination has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition.
  • the combination comprises, or alternatively consists essentially of, or yet further consists of one of the drug combinations selected from drug combinations 1-176 in Table 1.
  • Drugs in a drug combination used in the methods of some embodiments are administered sequentially or concurrently. In some embodiments, one, two, three, or four of drugs of a selected drug combination are administered sequentially. In some embodiments, one or two or three or four of the drugs of the selected drug combination are administered concurrently.
  • An administration schedule of the methods of some embodiments may be in a manner that provides a desirable therapeutic effect. For example, in some embodiments, a combination is administered once a day, twice a day or three times a day. In some embodiments, administration is continued for 2 or 4 or 6 or 8 weeks or more, or one, two, three, four or five months or more, or any value therein between. In some embodiments, the duration of treatment is less than 6 months of treatment, or less than 9, 12, 15, 18, 21 or 24 months.
  • a subject in need thereof is a mammal.
  • the mammal can be any mammal, including, for example, farm animals, sheep, pigs, cows, horses, pets, dogs, cats; laboratory animals, rats, mice and rabbits.
  • the mammal is a bovine, a feline, a canine, a murine, an equine, or a human .
  • the mammal is a human.
  • TB that is treated is caused by Mycobacterium
  • tuberculosis In other embodiments, the tuberculosis treated is caused by other species in the Mycobacterium tuberculosis complex. In some embodiments, the tuberculosis (TB) is caused by Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, or
  • TB is drug-sensitive TB or MDR-TB or XDR-TB. In some embodiments the TB is active TB. In some embodiments the TB is miliary TB. In some embodiments the TB is latent TB. In some embodiments the TB is latent TB.
  • a method of treating MDR-TB in a subject in need thereof comprising determining if a subject is infected with MDR-TB, and administering to the subject identified as infected with MDR-TB a pharmaceutical composition herein.
  • a method for treating MDR-TB in a subject in need thereof comprising administering a pharmaceutical composition herein, to the subject identified as being infected with MDR-TB.
  • a method of treating XDR-TB in a subject in need thereof comprising determining if a subject is infected with XDR-TB, and administering to the subject identified as infected with XDR-TB a pharmaceutical composition herein.
  • a method for treating XDR-TB in a subject in need thereof comprising administering a pharmaceutical composition herein to the subject identified as being infected with XDR-TB.
  • kits of drug combinations or as fixed dose combinations (FDCs) along with a pharmaceutically acceptable carrier or excipient.
  • FDCs fixed dose combinations
  • drugs in drug combinations can be combined into a single solid dose formulation for treating TB.
  • liquid or solid dose formulations may be used.
  • oral dose formulations include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like.
  • the compounds of some embodiments can be mixed with a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art.
  • suitable pharmaceutical carrier include starch, milk, sugar, certain types of clay, gelatin, lactic acid, stearic acid or salts thereof, including magnesium or calcium stearate, talc, vegetable fats or oils, gums and glycols.
  • formulations of the compounds useful in the methods of some embodiments may utilize conventional diluents, carriers, or excipients, which can be employed to deliver the compounds.
  • the formulations may comprise one or more of the following: a stabilizer, a surfactant (such as a nonionic, ionic, anionic, or zwitterionic surfactant), and optionally a salt and/or a buffering agent.
  • the compounds may be administered in the form of a solution, suspension, or in a reconstituted lyophilized form.
  • a stabilizer may be, for example, an amino acid, such as glycine; or an oligosaccharide, such as sucrose, trehalose, lactose or a dextran.
  • the stabilizer may be a sugar alcohol, such as mannitol; or a combination thereof.
  • Other stabilizers may include Beeswax, butylated hydroxytoluene, citric acid, ethyl vanillin, gelatin, glycerin, iron oxide, lecithin, p-methoxy acetophenone, parabens, plant oils, and propylene glycol.
  • the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% by weight/weight of a formulation.
  • a surfactant is a nonionic surfactant, such as a polysorbate.
  • suitable surfactants include polysorbates (e.g., Tween20, Tween80); a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001%) by weight/volume (w/v) to about 10%> (w/v).
  • a salt or buffering agent may be any suitable salt or buffering agent, such as sodium chloride, or sodium/potassium phosphate, respectively.
  • the buffering agent maintains the pH of the pharmaceutical composition in the range of about 5.5 to about 7.5.
  • the salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a human or other animal.
  • the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM.
  • the formulations of the compounds useful in the methods of this disclosure may additionally comprise one or more conventional additives.
  • additives include a solubilizer such as glycerol or hydroxypropyl-cyclodextrin; an antioxidant such as benzalkonium chloride (a mixture of quaternary ammonium compounds, referred to as "quats"), benzyl alcohol, chloretone or chlorobutanol; anesthetic agent such as a morphine derivative; or an isotonic agent.
  • a solubilizer such as glycerol or hydroxypropyl-cyclodextrin
  • an antioxidant such as benzalkonium chloride (a mixture of quaternary ammonium compounds, referred to as "quats"), benzyl alcohol, chloretone or chlorobutanol
  • anesthetic agent such as a morphine derivative
  • the formulations of the compounds useful in the methods of this disclosure are contained in a single vehicle (e.g., a single oral dose form).
  • a single oral dose formulation e.g., a single tablet, gelatin capsule, pill, troche, elixir, suspension, and so forth.
  • Stimulations can be applied to direct a complex system towards a desired state, such as applying drugs to treat a patient.
  • the types and the amplitudes (e.g., doses) of applying these stimulations are part of input parameters that can affect the efficiency in bringing the system towards the desired state.
  • N types of different drugs with different drug-doses for each drug will result in A f possible "drug-dose combinations.”
  • To identify an optimized or even near optimized combination by multiple tests of all possible drug-dose combinations is prohibitive in practice. For example, it is not practical to perform all the possible drug-dose combinations in in vitro or in vivo tests for finding an effective drug-dose combination as the number of drugs and dosages increase.
  • Embodiments of this disclosure apply a technique that allows a rapid search for optimized combinations of input parameters to guide multi-dimensional (or multivariate) systems with multiple input parameters toward their desired states.
  • the technique is comprised of a multi-dimensional complex system whose state is affected by input parameters along respective dimensions of a multi-dimensional parameter space.
  • the technique can efficiently operate on a large pool of input parameters (e.g., a drug pool), where the input parameters can involve complex interactions both among the parameters and with the complex system.
  • a search technique can be used to identify at least a subset, or all, optimized combinations or sub-combinations of input parameters that produce desired states of the complex system.
  • a parameter space sampling technique e.g., an experimental design methodology
  • a parameter space sampling technique can guide the selection of a minimal or reduced number of tests to expose salient features of the complex system being evaluated, and to reveal a combination or subcombination of input parameters of greater significance or impact in affecting a state of the complex system.
  • the is within Mycobacterium tuberculosis a macrophage.
  • the PRS optimization scheme is an Artificial Intelligence (AI) based PRS optimization scheme.
  • testing in step b) is done to reoptimize the in vivo doses.
  • an output (or a cost function) ⁇ is specified for a complex biological system being evaluated.
  • the output can be a function of X, which is a vector of input parameters in an input parameter space (e.g., a combination of doses of drugs sampled according to an experimental design methodology), and can be specified as an efficacy of a combinatorial drug or a percentage of inhibition.
  • Other outputs can be defined, such as a therapeutic window based on a viability of healthy control cells subjected to X and a viability of diseased cells subjected to X, where the former corresponds to safety of X, and the latter corresponds to efficacy of X, or including an interaction effect among drugs of X, to account for whether the drugs interact synergistically, antagonistically, or when the effect of the drugs is additive.
  • the output ⁇ represents an overall therapeutic outcome or response to be optimized (e.g., enhanced or maximized), and includes a combination (e.g., a weighted sum) of phenotypic contributions or responses, including either, or both, safety or toxicity when Xis applied to healthy control cells, and efficacy when Xis applied to diseased cells.
  • the output ⁇ can be represented as a response surface that is a function of input parameters within a multidimensional input parameter space.
  • Other relevant phenotypic contributions can be included in the output ⁇ by applying proper transformations to adjust a range and scale of the phenotypic contributions, such as those related to improved tolerance, enlarged therapeutic window, reduced drug dosages, and broad reduction of side effects.
  • phenotypic responses are desirable, such as drug efficacy or drug safety, while other phenotypic responses are undesirable, such as drug toxicity or drug side effects.
  • their weighting factors serve as penalty factors in the optimization of combinatorial drugs.
  • a response of a complex system to multiple input parameters can be represented by a low order function, such as a second order (or quadratic) equation, although a first order (or linear) equation as well as a third order (or cubic) equation are also contemplated as possible low order equations. Also, higher order functions are contemplated for other embodiments.
  • a low order function such as a second order (or quadratic) equation
  • a first order (or linear) equation as well as a third order (or cubic) equation are also contemplated as possible low order equations.
  • higher order functions are contemplated for other embodiments.
  • X is a dose of an z 'th drug from the pool of N drugs being evaluated
  • ⁇ is a coefficient representing a baseline response
  • ? is a coefficient representing a single drug response contribution
  • a coefficient is a coefficient.
  • i ⁇ j the terms represent drug-drug interaction contributions.
  • a total number of parameters m is 1 + 2N+ (N(N - l))/2. If one drug dose is kept constant in the evaluation, the number of parameters m can be further reduced to 1 + 2(TV- 1) +((N- l)(N- 2))/2, for TV > 1.
  • Table 2 sets forth a total number of coefficients in a quadratic cost function with respect to a total number drugs in a pool of drugs being evaluated.
  • An experimental design methodology is used to guide the selection of tests to sample an input parameter space.
  • the experimental design methodology can allow exposure of salient features of a complex system being evaluated, and can reveal a combination or subcombination of input parameters of greater significance or impact in affecting a state of the complex system. Selection of the experimental design methodology can be according to a particular cost function of the complex system being evaluated. Examples of experimental design methodologies include Latin hypercube sampling, central composite design, d-optimal design, orthogonal array design, full factorial design, and fractional factorial design, among others.
  • an experimental design methodology can be used to guide the selection of drug dosages for in vitro tests. In connection with the experimental design methodology, possible doses can be narrowed down into a few discrete levels.
  • therapeutic outcomes e.g., phenotypic responses
  • therapeutic outcomes are measured by testing each combination of input parameters sampled according to the experimental design methodology, such as by applying each combination of drug doses in vitro.
  • a representation of the cost function is fitted using values of the cost function measured or derived from the test results. Fitting of the cost function can be carried out by linear regression, Gaussian process regression, support vector machine regression, Bayesian regression, or another suitable technique. Based on the fitting performance between the test results and the fitted representation of the cost function, additional tests can be conducted to improve the accuracy of the fitted representation.
  • a globally or locally optimized combination of input parameters is determined or predicted using the fitted representation, such as by locating extrema using a stochastic or a deterministic optimization technique. Examples of stochastic techniques include simulated annealing, Markov chain Monte Carlo (MCMC), genetic optimization, differential evolution, and Gur game, among others. Examples of deterministic techniques include steepest descent and conjugate gradient, among others.
  • An optimized combination of input parameters predicted from a fitted representation can be experimentally verified, such as by applying the optimized combination in vitro, in vivo, or in clinical/human tests.
  • the significance of each input parameter and its synergistic effect with other input parameters can be identified.
  • Non-significant input parameters that have little or no impact in affecting a state of a complex system can be dropped or omitted from an initial pool of input parameters, thereby effectively converting an initial multi-dimensional system to a refined system with a lower dimensionality.
  • non-significant drugs can be identified as having low or negative values of the constants ?, ⁇ , ⁇ , and ⁇ , and can be dropped from an initial pool of drugs for subsequent evaluation.
  • Mtb-iGFP M tuberculosis Erdman inducible GFPuv strain
  • a pool of 15 drugs are evaluated, including the First-line drugs, Second-line Drugs, and Experimental TB drugs as follows:
  • Drug combinations are determined by experimental design methodology according to the PRS scheme. Monolayers are imaged with a high throughput
  • Table 3 PRS-projected inhibition of 3- and 4-drug combinations.
  • Table 4 tabulates the drug-dose combinations with their respective calculated inhibition.
  • Table 4 PRS-projected inhibition of 3- and 4-drug, drug dose combinations (including doses).

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Abstract

Pharmaceutical compositions including various drug combinations. Methods to inhibit the replication of tuberculosis (TB) causing bacteria in a cell. Methods of treating TB. Methods of determining an optimum dose of each drug in a drug combination of the disclosure.

Description

MULTI-DRUG THERAPIES FOR TUBERCULOSIS TREATMENT
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/485,859, filed April 14, 2017, which is incorporated herein by reference in its entirety.
BACKGROUND
[0002] The use of drug combinations possesses an important advantage over single drug therapy. Monotherapies often lead to disease recurrence and subsequent ineffectiveness of standard treatment due to drug resistance development. Multi-drug therapies are now the standard treatment for multiple diseases, but their development has involved arduous empirical testing. The design of such therapies is quite challenging since the interactions between drugs are not well understood, as the crossover between the affected cellular pathways is quite difficult to comprehend. Furthermore, combining several drugs at different possible concentrations or doses yields a large testing parametric space, which makes the search for an optimal combination a major challenge. Therefore, there is a need to use a different approach to develop multi-drug combinations.
[0003] It is against this background that a need arose to develop the embodiments described in this disclosure.
SUMMARY
[0004] In one aspect, provided is a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109. [0005] In another aspect, provided is a composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination selected from the group of drug combinations 1-176 tabulated in Table 1.
[0006] In another aspect, provided is a method to inhibit the replication of
Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum,
Mycobacterium canetti, or Mycobacterium microti, in a cell infected therewith, comprising, or alternatively consisting essentially of, or yet consisting of, contacting the cell with an effective amount of a pharmaceutical composition described herein.
[0007] In another aspect, provided is a method of treating tuberculosis (TB) in a subject in need thereof, comprising, or alternatively consisting essentially of, or yet consisting of, administering to the subject an effective amount of a pharmaceutical composition described herein.
[0008] In another aspect, provided is a pharmaceutical composition as described herein for use in the treatment of tuberculosis (TB) in a subject in need thereof.
[0009] In another aspect, provided is a method of determining the optimum drug-dose of each drug in the drug combination of claim 1, wherein the method comprises, or alternatively consists essentially of, or yet consists of: a) determining the optimal drug-dose combinations on the basis of in vitro studies on the efficacy of various drug-dose combinations in inhibiting Mycobacterium tuberculosis, using a Parabolic Response Surface (PRS) optimization scheme; b) testing optimal drug-dose combinations from a) having > 60% projected TB inhibition in a mouse model of pulmonary TB to determine the optimal drug-doses in vivo in a mouse, using the Parabolic Response Surface (PRS) optimization scheme; and c) extrapolating a human dose from optimal drug-doses in vivo in the mouse, using drug dose extrapolation techniques and mouse and human pharmacokinetic data for the drugs.
DETAILED DESCRIPTION
[0010] Currently, treatment for tuberculosis (TB) depends upon the drug sensitivity of the infecting strain of Mycobacterium tuberculosis and patient demographic (e.g., child, adult, pregnant, HIV-positive, and so forth). The two main classifications of TB treatment are "first-line" and "second-line". First-line treatment of drug-sensitive TB is a 4-drug regimen: isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Second-line treatments used to treat drug-resistant TB utilize 3-5 other drugs in combination:
aminoglycosides (amikacin (AMK), kanamycin (KM), and so forth), polypeptides (e.g., capreomycin, viomycin, and so forth), thioamides (e.g., ethioamide, prothioamide (PRO), and so forth), fluoroquinolones (e.g., ciprofloxacin (CIP), levofloxacin, moxifloxacin (MXF), and so forth), and cycloserine. There also are combination drugs or fixed-dose combinations (FDCs) used to help reduce the number of pills to be taken by patients during the TB treatment period. Examples of FDCs used for TB treatment include Rifater [isoniazid (INH), pyrazinamide (PZA), and rifampicin (RIF)] and Rifamate [isoniazid (INH) and rifampin (RIF)].
[0011] TB strains that are resistant to anti-TB drugs are increasingly being encountered. Approximately 450,000 people developed multi-drug resistant TB in 2012; half of the reported numbers were in India, China, and Russia. Multi-drug resistant TB (MDR-TB) is a categorization of strains of TB that are resistant to at least both isoniazid and rifampicin. MDR-TB arises from inappropriate treatment such as: use of poor quality medicines, administration of improper treatment regimens, and failing to ensure the patient has completed the whole course of treatment. Because MDR-TB is due to bacteria resistant to the two most powerful first-line anti-TB drugs, MDR-TB patients are then treated with first- line drugs to which the strain is sensitive plus several second-line drugs. However, second- line treatment options have their own sets of limitations and drawbacks: extensive chemotherapy, high cost, severe adverse drug reactions, and possible lack of availability. Furthermore, treatment with second-line drugs can lead to more severe drug resistance similar to the inappropriate treatment causing MDR-TB. Extensively drug-resistant TB (XDR-TB) is specified as MDR-TB that is additionally resistant to several other classes of anti-TB drugs including the most effective second-line anti-TB drugs. It is estimated that about 9.6% of reported MDR-TB cases are XDR-TB.
[0012] Embodiments of this disclosure are directed to a combination of drugs in respective doses, uses thereof and methods therewith for treating TB, and a method for determining the optimum drug doses in the combination. In some embodiments, the method for determining the optimum drug doses in the combination involves three stages. First, the optimal drug-dose combinations are determined on the basis of in vitro studies on the efficacy of various drug-dose combinations in inhibiting and in killing Mycobacterium tuberculosis, using a Parabolic Response Surface (PRS) [formerly Feedback System Control (FSC)] optimization scheme. Second, optimal combinations, namely those achieving > 60% projected TB inhibition, are tested in a mouse model of pulmonary TB to determine the optimal drug doses in vivo in the mouse, using the PRS approach. Finally, corresponding human doses can be extrapolated from mouse doses using drug dose extrapolation techniques and mouse and human pharmacokinetic data for the drugs.
Definitions
[0013] As used herein, the singular terms "a," "an," and "the" may include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an object can include multiple objects unless the context clearly dictates otherwise.
[0014] As used herein, the terms "substantially" and "about" are used to describe and account for small variations. When used in conjunction with an event or circumstance, the terms can refer to instances in which the event or circumstance occurs precisely as well as instances in which the event or circumstance occurs to a close approximation. For example, when used in conjunction with a numerical value, the terms can refer to a range of variation of less than or equal to ±10% of that numerical value, such as less than or equal to ±5%, less than or equal to ±4%, less than or equal to ±3%, less than or equal to ±2%, less than or equal to ±1%), less than or equal to ±0.5%, less than or equal to ±0.1%, or less than or equal to ±0.05%.
[0015] Additionally, amounts, ratios, and other numerical values are sometimes presented herein in a range format. It is to be understood that such range format is used for
convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly specified. For example, a range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual values such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth. [0016] In some embodiments, clofazimine (CLZ) corresponds to N,5-bis(4- chlorophenyl)-3-(propan-2-ylimino)-3,5-dihydrophenazin-2-amine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0001
[0017] In some embodiments, ethambutol (EMB) corresponds to (2,S',2')S)-2,2'-(ethane- l,2-diyldiimino)dibutan-l-ol, and is represented by the following structure, or a
pharmaceutically acceptable salt thereof:
Figure imgf000006_0002
[0018] In some embodiments, pretomanid (PA824) corresponds to (6,S)-2-nitro-6-{[4- (trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,l-^][l,3]oxazine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000006_0003
[0019] In some embodiments, pyrazinamide (PZA) corresponds to pyrazine-2- carboxamide, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0001
[0020] In some embodiments, rifampin (RIF) is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0002
[0021] In some embodiments, SQ109 corresponds to N-adamantan^-yl-N'-^ ^-S,?- dimethyl-octa-2,6-dienyl)-ethane-l,2-diamine, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0003
[0022] In some embodiments, bedaquiline (BDQ) corresponds to (li?,2,S)-l-(6-bromo-2- methoxy-3-quinolyl)-4-dimethylamino-2-(l-naphthyl)-l-phenyl-butan-2-ol, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000007_0004
[0023] In some embodiments, amoxicillin corresponds to (2S,5R, 6R)-6-{ [(2R)-2-amino- 2-(4-hydroxyphenyl)-acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane- 24-carboxylic acid, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
[0024] In some embodiments, clavulanic acid corresponds to (2R,5R,Z)-3-(2- hydroxyethylidene)-7-oxo-4-oxa-l-aza-bicyclo[3.2.0]heptane-2-carboxylic acid, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0002
[0025] In some embodiments, delamanid (OPC or OPC-67683) corresponds to (2R)-2- methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy)phenoxy]-l-piperidinyl}phenoxy)methyl]-2,3- dihydroimidazo[2, l-6][l,3]oxazole, and is represented by the following structure, or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0003
[0026] As used herein, "linezolid" corresponds to (,S)-N-({3-[3-fluoro-4-(morpholin-4- yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide and is represented by the following structure or a pharmaceutically acceptable salt thereof:
Figure imgf000009_0001
[0027] Those of ordinary skill in the art will appreciate that compounds of some embodiments may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or optical isomerism. Although chemical structures within the specification and claims may represent one of multiple possible tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms, it should be understood that this disclosure encompasses any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.
[0028] "Tautomers" refer to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on an environment in which the compound is found and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Figure imgf000009_0002
[0029] As will be understood by one of ordinary skill in the art, a wide variety of functional groups and other chemical structures may exhibit tautomerism, and all tautomers of compounds as described herein are within the scope of this disclosure.
[0030] Stereoisomers of compounds, also referred to as "optical isomers," include all chiral, diastereomeric, and racemic forms of a chemical structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in some embodiments include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of this disclosure.
[0031] The term "pharmaceutically acceptable" refers to a material that is not
biologically or otherwise undesirable, namely the material may be incorporated into a pharmaceutical composition administered to a patient without causing undesirable biological effects or interacting in a deleterious manner with any of other components of the
composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, the carrier or excipient is one that has met standards of toxicological and manufacturing testing or that is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
[0032] The term "extrapolation technique" refers to extrapolation types including, but not limited to linear extrapolation, polynomial, conic section or French curve extrapolation.
[0033] "Pharmacokinetic data" for drugs disclosed herein includes data comprising serum levels, tissue levels, metabolism, binding affinities, and bioavailability. Pharmacokinetic data may be acquired through analytical techniques including but not limited to immunoassay, mass spectrometry, MR spectroscopy, spectrophotometry, chromatography, diode array detection, capillary electrophoresis, enzyme linked immunosorbent assay, or
radioimmunoassay.
[0034] "Macrophage" refers to a type of phagocytotic white blood cell of the immune system. Such machines can perceive their environment and take actions based on what is perceived.
[0035] "Artificial Intelligence" or "AI" as used herein refers to intelligence demonstrated by machines. Machines with AI may display treats such as learning and memory.
[0036] An "effective amount" is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations or applications. Such delivery is dependent on a number of variables including the time period for which the individual composition is to be used, the bioavailability of the therapeutic agents included with the composition, the route of administration, etc. It is understood, however, that specific dose levels of the additional therapeutic agents disclosed herein for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal/subject and its body weight, general health, sex, the diet of the animal/subject, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition and as used herein, the term "therapeutically effective amount" or "pharmaceutically effective amount" is an amount sufficient to treat a specified disorder or disease or alternatively to obtain a pharmacological response such as immunosuppression, osteogenesis, bone resorption or mineralization.
[0037] The term "patient" refers to any animal for which treatment is desirable. Patients may be mammals, and typically, as used herein, a patient is a human individual. "Patient" and "subject" are to be understood to be interchangeable.
[0038] "TB inhibition" refers to a percentage determined via an inhibition assay, also referred to herein as a "treatment test" described in the working examples which quantifies bacteria via fluorescence or alternatively, by the quantification or colony forming unites (CFUs) as described in the working examples.
[0039] Administration or treatment in "combination" refers to administering two agents such that their pharmacological and/or therapeutic effects are manifest at the same time. Combination does not require administration at the same time or substantially the same time, although combination can include such administrations. Combination can include sequential administration.
[0040] "Replication" refers to the division of bacterial cells or the replication, copying, or transcription of their genetic material including deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and the like.
[0041] "Contacting" as used herein refers to introduction of a drug, agent, or
pharmaceutical composition to that which it contacts. Contacting may be accomplished by "administration" through any of the means described herein. [0042] As used herein, "treating" or "treatment" of a disease in a subject refers to (1) preventing the symptoms or disease from occurring in a subject that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease or the symptoms of the disease. As understood in the art, "treatment" is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of the present technology, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease or trauma), stabilized (i.e., not worsening) state of a condition (including disease or trauma), delay or slowing of condition (including disease or trauma), progression, amelioration or palliation of the condition (including disease or trauma), states and remission (whether partial or total), whether detectable or undetectable.
[0043] The terms "inhibits," "inhibiting," and the like, as used herein, refer to attenuating, halting, reversing or attenuating the acceleration of that to which they refer. As used herein these terms may refer to attenuating, halting, reversing or attenuating the acceleration of bacterial replication or killing the bacteria.
[0044] "Administration," "administering" intends local or systemic administration. In some embodiments administration is systemic via, intracerebroventricular, intrathecal, topical, intravenous, intranasal, subcutaneous, intramuscular, or transdermal administration. Local administration is surgical implantation of the compositions described herein.
Administration may be accomplished implanting the pharmaceutical composition directly or coating or impregnating a surgical implant or prosthesis with the pharmaceutical
compositions of the disclosure. The pharmaceutical compositions may be implanted anywhere throughout the body
[0045] "Drug," drugs" and the like or "compound," "compounds" and the like, as used herein, refers to a substance administered to a subject. Drugs of this disclosure are tabulated in Table 1 and described herein. A combination of two substances may together be referred to as a single "drug," for example the combination of amoxicillin/clavulanic acid (A/C), is a "drug."
[0046] The term "drug-dose combination," "drug dose combination," or 'drug dose," or "drug-dose" and the like refer to a data set including a drug combination and a dose for each respective drug of the drug combination. The doses for each drug in a drug dose-combination can be determined by methods described herein, for example PRS optimization scheme, in vitro, or in vivo testing. A drug dose combination can be expressed in terms of a specific mass or concentration in a solution for each drug. The drug dose combination can be expressed as a ratio of the drugs of a combination. Various drug dose combinations, are tabulated in Table 4 herein.
[0047] "Drug combination" refers to a combination of three or more drugs which together comprise the "pharmaceutical composition" of the disclosure. Each row 1-176 of Table 1 discloses a "drug combination." For example, the first row of Table 1 discloses the drug combination: ethambutol, PA824, rifampicin and OPC. A " pharmaceutical composition" typically intends a combination of the active agent(s), e.g., drug(s), and a naturally-occurring or non-naturally-occurring carrier, inert (for example, a detectable agent or label) or active, such as an adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant or the like and include pharmaceutically acceptable carriers. Carriers also include pharmaceutical excipients and additives proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-oligosaccharides, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1-99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid/antibody
components, which can also function in a buffering capacity, include alanine, arginine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this technology, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D- mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol) and myoinositol.
[0048] The term "pharmaceutically acceptable salt," as used herein, represents salts or zwitterionic forms of compounds of some embodiments, which are water or oil-soluble or dispersible, which are suitable for treatment of diseases without undue toxicity, irritation, and allergic-response, which are commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use. The salts can be prepared during a final isolation and purification of the compounds or separately by reacting an appropriate compound in the form of a free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, di gluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds of some embodiments can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, this disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds of some embodiments and the like.
[0049] The term "solvate" is used in its broadest sense. For example, solvates include hydrates formed when a compound of some embodiments contains one or more bound water molecules.
Drug Combinations
[0050] Some embodiments of this disclosure include various combinations of known drugs. The combinations show improved efficacy against TB compared with conventional treatments. In some embodiments, multiple optimal drug-dose combinations are determined on the basis of in vitro studies and PRS analysis. Certain embodiments of drug combinations have been evaluated on the basis of in vitro TB treatment tests, and achieve > 60% projected TB inhibition.
[0051] In one aspect, provided is a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109.
[0052] In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and OPC. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and A/C. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and SQ109.
[0053] In some embodiments, a drug combination is selected from one of the following drug combinations of Table 1, 1-176:
Table 1: Drug combinations 1-176
1 Ethambutoi PA824 Rifampicin OPC
2 A/C Ethambutoi Rifampicin OPC
3 Clofazimine Ethambutoi Rifampicin OPC
4 A/C Ethambutoi PA824 Rifampicin
5 A/C Clofazimine Ethambutoi Rifampicin
6 Ethambutoi Rifampicin Bedaquiline OPC
7 Ethambutoi PA824 Rifampicin Bedaquiline
8 Clofazimine PA824 Rifampicin OPC
9 PA824 Rifampicin SQ109 OPC
10 A/C PA824 Rifampicin OPC
1 1 AC Ethambutoi Rifampicin Bedaquiline
12 Ethambutoi Rifampicin OPC
13 Clofazimine PA824 SQI 09 OPC
14 Clofazimine Ethambutoi Pyrazinamide Rifampicin
15 A/C Ethambutoi Pyrazinamide Rifampicin
16 Ethambutoi Pyrazinamide Rifampicin OPC PA824 Rifampicin Bedaquiiine OPC
Ethambutol PA 824 Rifampicin
Clofazimine Ethambutol PA824 OPC
Clofazimine Ethambutol Rifampicin Bedaquiiine
Ethambutol PA824 Rifampicin SQ 109
AJC Ethambutol PA824 OPC
Clofazimine Ethambutol Rifampicin
A/C Ethambutol Rifampicin
AJC Clofazimine Rifampicin OPC
PA824 Pyrazinamide Rifampicin OPC
Clofazimine Pyrazinamide SQ 109 OPC
Clofazimine Pyrazinamide Rifampicin OPC
A/C Clofazimine Ethambutol OPC
Clofazimine Rifampicin SQ 109 OPC
PA824 Pyrazinamide Rifampicin
Ethambutol
A/C Pyrazinamide Rifampicin OPC
PA824 Rifampicin OPC
A/C Clofazimine PA824 OPC
Ethambutol Rifampicin SQ109 OPC
A/C Rifampicin SQ109 OPC
A/C Clofazimine Pyrazinamide OPC
Clofazimine PA824 Pyrazinamide OPC
A/C Clofazimine Ethambutol PA824
Ethambutol Pyrazinamide Rifampicin Bedaquiiine
A/C Clofazimine Ethambutol Pyrazinamide
A/C Rifampicin Bedaquiiine OPC
Pyrazinamide Rifampicin SQ109 OPC
Ethambutol PA824 Bedaquiiine OPC
A/C Ethambutol Rifampicin SQ109
A/C Clofazimine Pyrazinamide SQ109
Ethambutol Rifampicin Bedaquiiine
A/C Clofazimine SQ109 OPC
Clofazimine Ethambutol Pyrazinamide 0
Ethambutol Pyrazinamide Rifampicin
Clofazimine Rifampicin OPC
A/C PA824 SQ109 OPC
PA824 Pyrazinamide Rifampicin SQ109
Pyrazinamide Rifampicin Bedaquiiine OPC
Rifampicin SQ109 Bedaquiiine OPC
Clofazimine PA824 Bedaquiiine OPC
A/C Rifampicin OPC A/C Ethambutol Bedaquiline OPC
PA824 Rifampicin SQ109 Bedaquiline
A/C Clofazimine Pyrazinamide Rifampicin
Ethambutol Pyrazinamide Rifampicin SQ109
Clofazimine PA824 Pyrazinamide Rifampicin
PA824 SQ109 Bedaquiline OPC
A/C PA824 Bedaquiline OPC
PA824 Pyrazinamide SQ109 OPC
A/C Clofazimine PA824 SQ109
Clofazimine PA824 OPC
A/C PA824 Pyrazinamide OPC
A/C PA824 Rifampicin SQ109
A C Clofazimine PA824 Rifampicin
A/C Ethambutol PA824 Bedaquiline
Clofazimine Ethambutol Bedaquiline OPC
A/C Ethambutol Pyrazinamide OPC
Clofazimine Ethambutol SQ109 OPC
Clofazimine Ethambutol OPC
A/C Clofazimine Ethambutol Bedaquiline
Ethambutol Rifampicin SQ109
Clofazimine Ethambutol PA824
Pyrazinamide Rifampicin OPC
A/C Clofazimine Ethambutol SQ109
Rifampicin SQ109 OPC
Ethambutol PA824 SQ109 OPC
A/C Clofazimine Rifampicin SQ109
Ethambutol PA824 OPC
A/C Clofazimine Ethambutol
A/C PA824 Pyrazinamide Rifampicin
Clofazimine SQ109 Bedaquiline OPC
PA824 Rifampicin SQ109
A/C Clofazimine PA824 Pyrazinamide
Clofazimine PA824 SQ109
A/C Pyrazinamide Rifampicin SQ109
Clofazimine Pyrazinamide Bedaquiline OPC
Clofazimine SQ109 OPC
A/C Rifampicin SQ109 Bedaquiline
Clofazimine PA824 Rifampicin Bedaquiline
A/C PA824 Rifampicin Bedaquiline 98 Ethambutol PA824 Pyrazinamide OPC
99 Clofazimine Pyrazinamide OPC
100 Clofazimine PA824 Rifampicin
101 A/C PA824 SQ109 Bedaquiline
102 Clofazimine Ethambutol Pyrazinamide
103 Rifampicin Bedaquiline OPC
104 A/C Clofazimine Bedaquiline OPC
105 A/C Ethambutol PA824 Pyrazinamide
106 PA824 Pyrazinamide Rifampicin Bedaquiline
107 Pyrazinamide Rifampicin SQ109 Bedaquiline
108 PA824 Pyrazinamide Bedaquiline OPC
109 A/C Clofazimine OPC
110 A/C Ethambutol OPC
1 11 A/C Rifampicin SQ109
112 Clofazimine Rifampicin SQ109
1 13 Clofazimine Pyrazinamide Rifampicin Bedaquiline
114 A/C Pyrazinamide SQ109 OPC
115 A/C Pyrazinamide Rifampicin Bedaquiline
116 Clofazimine Pyrazinamide Rifampicin
117 PA824 SQ109 OPC
1 18 A/C PA824 OPC
1 19 A/C Ethambutol PA824 SQ109
120 A/C PA824 Rifampicin
121 A/C Ethambutol PA824
122 A/C Pyrazinamide Bedaquiline OPC
123 A/C Ethambutol Pyrazinamide Bedaquiline
124 Clofazimine Ethambutol SQ109
125 A/C Clofazimine Pyrazinamide Bedaquiline
126 Clofazimine PA824 Pyrazinamide Bedaquiline
127 A/C Clofazimine Rifampicin Bedaquiline
128 PA824 Pyrazinamide Rifampicin
129 Pyrazinamide Rifampicin SQ109
131 A/C PA824 Pyrazinamide SQ109
132 A/C Clofazimine Rifampicin
133 A/C Clofazimine Pyrazinamide
134 A/C SQ109 Bedaquiline
135 A/C SQ109 Bedaquiline OPC
136 Clofazimine PA824 Pyrazinamide
137 A/C Pyrazinamide Rifampicin 138 PA824 Rifampicin Bedaquiline
139 A/C Clofazimine SQ109 Bedaquiline
140 Ethambutol Pyrazinamide Bedaquiline OPC
141 Ethambutol PA824 Pyrazinamide Bedaquiline
142 PA824 SQ109 Bedaquiline
143 Pyrazinamide SQ109 Bedaquiline OPC
144 A/C Clofazimine PA824 Bedaquiline
145 PA824 Bedaquiline OPC
146 Clofazimine Ethambutol Bedaquiline
147 A/C Clofazimine SQ109
148 PA824 Pyrazinamide OPC
149 Ethambutol PA824 Pyrazinamide SQ109
150 Rifampicin SQ109 Bedaquiline
15 1 Ethambutol PA824 Bedaquiline
152 A C Clofazimine PA824
153 A/C Ethambutol Pyrazinamide SQ109
154 Ethambutol SQ109 Bedaquiline OPC
155 Ethambutol Bedaquiline OPC
156 A/C Pyrazinamide OPC
157 A C Ethambutol Pyrazinamide
158 A/C Ethambutol SQ109 Bedaquiline
159 Ethambutol PA824 SQ109
160 Clofazimine Bedaquiline OPC
161 A/C PA824 Pyrazinamide Bedaquiline
162 A/C Ethambutol Bedaquiline
163 Clofazimine Rifampicin Bedaquiline
164 Pyrazinamide Rifampicin Bedaquiline
165 A C Rifampicin Bedaquiline
166 A/C Bedaquiline OPC
167 Ethambutol Pyrazinamide SQ109 OPC
168 A/C Pyrazinamide SQ109 Bedaquiline
169 Ethambutol Pyrazinamide OPC
170 Ethambutoi PA824 Pyrazinamide
171 A/C PA824 SQ109
172 PA824 Pyrazinamide SQ109
173 Pyrazinamide SQ109 OPC
174 A/C SQ109 OPC
175 Clofazimine PA824 Bedaquiline
176 Clofazimine Pyrazinamide Bedaquiline [0054] In Table 1, PA824 denotes pretomanid, OPC denotes OPC-67683 or delamanid, A/C denotes a combination of amoxicillin/clavulanic acid, and SQ109 denotes N-Adamantan- 2-yl-N'-((JE)-3,7-dimethyl-octa-2,6-dienyl)-ethane-l,2-diamine.
[0055] In some embodiments the pharmaceutical composition comprises, consists essentially of, or yet consists of one or more carriers. In some embodiments, the drugs are combined into a single solid dose formulation. In some embodiments the drugs are present in the same ratio as they are in each drug-dose combination of Table 4.
[0056] In some embodiments, the pharmaceutical composition comprises, consists essentially of, or yet consists a drug dose combination corresponding to a row of Table 4. In some embodiments the drugs are in solution at a concentration according to Table 4. In some embodiments, the drugs in the pharmaceutical composition are present in a ratio of their concentrations in Table 4 relative to each other.
[0057] In some embodiments, the drug combinations provide at least one of a number of benefits, including one or more of the following. First, the drug combinations are treatment combinations that can have higher efficacy than other drug combinations used for TB treatment. Second, the drug combinations provide alternative combinations for the treatment of drug-resistant TB, and also allow faster treatment of drug-resistant TB. Since many of the drug combinations do not include INH and RTF, alternative regimens can be developed that are suitable for the treatment of many cases of MDR-TB. Surprisingly, even though many of the drug combinations do not include the two most powerful first-line anti-TB drugs, INH and RTF, those combinations are shown to be superior to the standard regimen. Moreover, because the regimens do not include, or can omit, fluoroquinolones or aminoglycosides, the regimens also can be useful for treatment of many cases of XDR-TB. Third, current drug treatment regimen generally requires 6-8 months of treatment. Treatment of drug-resistant strains takes even longer, typically 24 months. Because treatment is so prolonged, patient compliance is often poor. Poor patient compliance increases the likelihood of drug resistance developing. The proposed drug-dose combinations of this disclosure allow more rapid and more efficacious treatment of both drug-sensitive and drug-resistant TB and greater patient compliance.
[0058] In one aspect, provided is a pharmaceutical composition comprising, or alternatively consisting essentially of, or yet consisting of, a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises, or consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises, consists essentially of, or yet consists of, a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109; for use in the treatment of TB in a subject in need thereof.
[0059] In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, and pyrazinamide. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and OPC. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and A/C. In some embodiments, the drug combination comprises, consists essentially of, or yet consists of, clofazimine, bedaquiline, pyrazinamide, and SQ109.
[0060] In some embodiments the pharmaceutical composition comprises, consists essentially of, or yet further consists of a drug combination that has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition.
[0061] In some embodiments, treatment comprises, consists essentially of, or yet further consists of administering two or more drugs of the drug combination sequentially. In some embodiments, treatment comprises, consists essentially of, or yet further consists of administering two or more drugs of the drug combination concurrently.
[0062] In some embodiments the subject is a mammal, including, for example, farm animals, sheep, pigs, cows, horses, pets, dogs, cats; laboratory animals, rats, mice and rabbits. In some embodiments, the mammal is a bovine, a feline, a canine, a murine, an equine, or a human . In some embodiments, the mammal is a human.
[0063] In some embodiments, TB that is treated is caused by Mycobacterium
tuberculosis. In other embodiments, the tuberculosis treated is caused by other species in the Mycobacterium tuberculosis complex. In some embodiments, the tuberculosis (TB) is caused by Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, or
Mycobacterium microti. In some embodiments, TB is drug-sensitive TB or MDR-TB or XDR-TB. In some embodiments the TB is active TB. In some embodiments the TB is miliary TB. In some embodiments, the TB is pulmonary TB. In some embodiments the TB is latent TB.
[0064] In some embodiments the drugs are each independently administered once a day, twice a day or three times a day. In some embodiments, each drug's administration is independently continued for 2 or 4 or 6 or 8 weeks or more, or one, two, three, four or five months or more, or any value therein between. In some embodiments each drug's administration is independently continued for less than 6 months, or less than 9, 12, 15, 18, 21 or 24 months.
Methods
[0065] Some embodiments of this disclosure include methods of treating TB in a patient or other subject in need thereof, comprising, or alternatively consisting essentially of, or yet further consisting of, administering to the patient a pharmaceutically effective amount of a pharmaceutical composition or drug combination described herein. In some embodiments, the drug combination has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition. In some embodiments, the combination comprises, or alternatively consists essentially of, or yet further consists of one of the drug combinations selected from drug combinations 1-176 in Table 1.
[0066] Drugs in a drug combination used in the methods of some embodiments are administered sequentially or concurrently. In some embodiments, one, two, three, or four of drugs of a selected drug combination are administered sequentially. In some embodiments, one or two or three or four of the drugs of the selected drug combination are administered concurrently.
[0067] An administration schedule of the methods of some embodiments may be in a manner that provides a desirable therapeutic effect. For example, in some embodiments, a combination is administered once a day, twice a day or three times a day. In some embodiments, administration is continued for 2 or 4 or 6 or 8 weeks or more, or one, two, three, four or five months or more, or any value therein between. In some embodiments, the duration of treatment is less than 6 months of treatment, or less than 9, 12, 15, 18, 21 or 24 months.
[0068] In some embodiments, a subject in need thereof is a mammal. The mammal can be any mammal, including, for example, farm animals, sheep, pigs, cows, horses, pets, dogs, cats; laboratory animals, rats, mice and rabbits. In some embodiments, the mammal is a bovine, a feline, a canine, a murine, an equine, or a human . In some embodiments, the mammal is a human.
[0069] In some embodiments, TB that is treated is caused by Mycobacterium
tuberculosis. In other embodiments, the tuberculosis treated is caused by other species in the Mycobacterium tuberculosis complex. In some embodiments, the tuberculosis (TB) is caused by Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, or
Mycobacterium microti. In some embodiments, TB is drug-sensitive TB or MDR-TB or XDR-TB. In some embodiments the TB is active TB. In some embodiments the TB is miliary TB. In some embodiments the TB is latent TB. In some embodiments the TB is latent TB.
[0070] In one aspect, provided is a method of treating MDR-TB in a subject in need thereof, the method comprising determining if a subject is infected with MDR-TB, and administering to the subject identified as infected with MDR-TB a pharmaceutical composition herein. In another aspect, provided is a method for treating MDR-TB in a subject in need thereof comprising administering a pharmaceutical composition herein, to the subject identified as being infected with MDR-TB.
[0071] In one aspect, is provided a method of treating XDR-TB in a subject in need thereof, the method comprising determining if a subject is infected with XDR-TB, and administering to the subject identified as infected with XDR-TB a pharmaceutical composition herein. In another aspect is provided a method for treating XDR-TB in a subject in need thereof comprising administering a pharmaceutical composition herein to the subject identified as being infected with XDR-TB.
Formulations
[0072] Some embodiments of this disclosure can be implemented as kits of drug combinations or as fixed dose combinations (FDCs) along with a pharmaceutically acceptable carrier or excipient. For example, drugs in drug combinations can be combined into a single solid dose formulation for treating TB.
[0073] For oral administration, liquid or solid dose formulations may be used. Some examples of oral dose formulations include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like. The compounds of some embodiments can be mixed with a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art. Examples of carriers and excipients include starch, milk, sugar, certain types of clay, gelatin, lactic acid, stearic acid or salts thereof, including magnesium or calcium stearate, talc, vegetable fats or oils, gums and glycols.
[0074] For systemic, intracerebroventricular, intrathecal, topical, intravenous, intranasal, subcutaneous, intramuscular, or transdermal administration, formulations of the compounds useful in the methods of some embodiments may utilize conventional diluents, carriers, or excipients, which can be employed to deliver the compounds. For example, the formulations may comprise one or more of the following: a stabilizer, a surfactant (such as a nonionic, ionic, anionic, or zwitterionic surfactant), and optionally a salt and/or a buffering agent. The compounds may be administered in the form of a solution, suspension, or in a reconstituted lyophilized form.
[0075] In some embodiments, a stabilizer may be, for example, an amino acid, such as glycine; or an oligosaccharide, such as sucrose, trehalose, lactose or a dextran. Alternatively, the stabilizer may be a sugar alcohol, such as mannitol; or a combination thereof. Other stabilizers may include Beeswax, butylated hydroxytoluene, citric acid, ethyl vanillin, gelatin, glycerin, iron oxide, lecithin, p-methoxy acetophenone, parabens, plant oils, and propylene glycol. In some embodiments, the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% by weight/weight of a formulation.
[0076] In some embodiments, a surfactant is a nonionic surfactant, such as a polysorbate. Some examples of suitable surfactants include polysorbates (e.g., Tween20, Tween80); a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001%) by weight/volume (w/v) to about 10%> (w/v).
[0077] A salt or buffering agent may be any suitable salt or buffering agent, such as sodium chloride, or sodium/potassium phosphate, respectively. In some embodiments, the buffering agent maintains the pH of the pharmaceutical composition in the range of about 5.5 to about 7.5. The salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a human or other animal. In some embodiments, the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM. [0078] The formulations of the compounds useful in the methods of this disclosure may additionally comprise one or more conventional additives. Some examples of such additives include a solubilizer such as glycerol or hydroxypropyl-cyclodextrin; an antioxidant such as benzalkonium chloride (a mixture of quaternary ammonium compounds, referred to as "quats"), benzyl alcohol, chloretone or chlorobutanol; anesthetic agent such as a morphine derivative; or an isotonic agent. As a further precaution against oxidation or other spoilage, the pharmaceutical compositions may be stored under nitrogen gas in vials sealed with impermeable stoppers.
[0079] In some embodiments, the formulations of the compounds useful in the methods of this disclosure are contained in a single vehicle (e.g., a single oral dose form). For example, the pharmaceutical composition comprising a drug combination of useful in the methods of this disclosure may be provided in a single oral dose formulation (e.g., a single tablet, gelatin capsule, pill, troche, elixir, suspension, and so forth).
Parabolic Response Surface (PRS) Optimization Scheme
[0080] Stimulations can be applied to direct a complex system towards a desired state, such as applying drugs to treat a patient. The types and the amplitudes (e.g., doses) of applying these stimulations are part of input parameters that can affect the efficiency in bringing the system towards the desired state. However, N types of different drugs with different drug-doses for each drug will result in A f possible "drug-dose combinations." To identify an optimized or even near optimized combination by multiple tests of all possible drug-dose combinations is prohibitive in practice. For example, it is not practical to perform all the possible drug-dose combinations in in vitro or in vivo tests for finding an effective drug-dose combination as the number of drugs and dosages increase.
[0081] Embodiments of this disclosure apply a technique that allows a rapid search for optimized combinations of input parameters to guide multi-dimensional (or multivariate) systems with multiple input parameters toward their desired states. The technique is comprised of a multi-dimensional complex system whose state is affected by input parameters along respective dimensions of a multi-dimensional parameter space. In some embodiments, the technique can efficiently operate on a large pool of input parameters (e.g., a drug pool), where the input parameters can involve complex interactions both among the parameters and with the complex system. A search technique can be used to identify at least a subset, or all, optimized combinations or sub-combinations of input parameters that produce desired states of the complex system. Taking the case of combinational drugs, for example, a large number of drugs can be evaluated to rapidly identify optimized combinations, ratios, and doses of drugs. A parameter space sampling technique (e.g., an experimental design methodology) can guide the selection of a minimal or reduced number of tests to expose salient features of the complex system being evaluated, and to reveal a combination or subcombination of input parameters of greater significance or impact in affecting a state of the complex system.
[0082] In one aspect provided is a method of determining the optimum drug-dose of each drug in the drug combination of this disclosure, wherein the method comprises: a)
determining the optimal drug-dose combinations on the basis of in vitro studies on the efficacy of various drug-dose combinations in inhibiting Mycobacterium tuberculosis, using a Parabolic Response Surface (PRS) optimization scheme; b) testing optimal drug-dose combinations from a) having > 60% projected TB inhibition in a mouse model of pulmonary TB to determine the optimal drug-doses in vivo in the mouse, using the Parabolic Response Surface (PRS) optimization scheme; and c) extrapolating a human dose from optimal drug- doses in vivo in the mouse, using a drug dose extrapolation technique and mouse and human pharmacokinetic data for the drugs. In some embodiments, the is within Mycobacterium tuberculosis a macrophage. In some embodiments the PRS optimization scheme is an Artificial Intelligence (AI) based PRS optimization scheme. In some embodiments testing in step b) is done to reoptimize the in vivo doses.
[0083] In some embodiments, an output (or a cost function)^ is specified for a complex biological system being evaluated. Taking the case of combinational drugs tested on cell cultures, for example, the output can be a function of X, which is a vector of input parameters in an input parameter space (e.g., a combination of doses of drugs sampled according to an experimental design methodology), and can be specified as an efficacy of a combinatorial drug or a percentage of inhibition. Other outputs can be defined, such as a therapeutic window based on a viability of healthy control cells subjected to X and a viability of diseased cells subjected to X, where the former corresponds to safety of X, and the latter corresponds to efficacy of X, or including an interaction effect among drugs of X, to account for whether the drugs interact synergistically, antagonistically, or when the effect of the drugs is additive. The output^ represents an overall therapeutic outcome or response to be optimized (e.g., enhanced or maximized), and includes a combination (e.g., a weighted sum) of phenotypic contributions or responses, including either, or both, safety or toxicity when Xis applied to healthy control cells, and efficacy when Xis applied to diseased cells. The output^ can be represented as a response surface that is a function of input parameters within a multidimensional input parameter space. Other relevant phenotypic contributions can be included in the output^ by applying proper transformations to adjust a range and scale of the phenotypic contributions, such as those related to improved tolerance, enlarged therapeutic window, reduced drug dosages, and broad reduction of side effects. Certain phenotypic responses are desirable, such as drug efficacy or drug safety, while other phenotypic responses are undesirable, such as drug toxicity or drug side effects. In the case of the latter phenotypic responses, their weighting factors serve as penalty factors in the optimization of combinatorial drugs.
[0084] In some embodiments, a response of a complex system to multiple input parameters can be represented by a low order function, such as a second order (or quadratic) equation, although a first order (or linear) equation as well as a third order (or cubic) equation are also contemplated as possible low order equations. Also, higher order functions are contemplated for other embodiments. Taking the case of combinational drugs, for example, an overall therapeutic response (as represented by the output^) can be specified as a function of drug doses as follows: y = β +∑ βίΧί +∑ βί/ΧΧί' + higher order terms
i ϋ '
where X is a dose of an z'th drug from the pool of N drugs being evaluated, βο is a coefficient representing a baseline response, ?, is a coefficient representing a single drug response contribution, is a coefficient. When i≠ j, the terms represent drug-drug interaction contributions. When i = j, the terms represent the non-linear effects of the drugs. The summations run through N. If cubic and other higher order terms are omitted, then the output y can be represented by a quadratic equation of the drug doses X. As noted above, other representations, including third and higher order functions or the use of linear regression, are also contemplated.
For the case of N= 1 (a pool of 1 drug), then: y = βο + βιΧ + βιιΧιΧι
with a total of three constants, βο, βι , and βη.
For the case of N= 2 (a pool of 2 drugs), then: y = βο + βιΧι + β2Χ2 + β 12 1 2 + βπΧιΧι + β22Χ2Χ2
with a total of six constants, βο, βι, ¾, βη, βιι, and ¾ -
[0085] More generally for TV total drugs, a total number of parameters m is 1 + 2N+ (N(N - l))/2. If one drug dose is kept constant in the evaluation, the number of parameters m can be further reduced to 1 + 2(TV- 1) +((N- l)(N- 2))/2, for TV > 1. Table 2 below sets forth a total number of coefficients in a quadratic cost function with respect to a total number drugs in a pool of drugs being evaluated.
Table 2
Figure imgf000028_0001
[0086] An experimental design methodology is used to guide the selection of tests to sample an input parameter space. The experimental design methodology can allow exposure of salient features of a complex system being evaluated, and can reveal a combination or subcombination of input parameters of greater significance or impact in affecting a state of the complex system. Selection of the experimental design methodology can be according to a particular cost function of the complex system being evaluated. Examples of experimental design methodologies include Latin hypercube sampling, central composite design, d-optimal design, orthogonal array design, full factorial design, and fractional factorial design, among others. In the case of combinational drugs, for example, an experimental design methodology can be used to guide the selection of drug dosages for in vitro tests. In connection with the experimental design methodology, possible doses can be narrowed down into a few discrete levels.
[0087] Once tests are designed, therapeutic outcomes (e.g., phenotypic responses) are measured by testing each combination of input parameters sampled according to the experimental design methodology, such as by applying each combination of drug doses in vitro.
[0088] Next, a representation of the cost function is fitted using values of the cost function measured or derived from the test results. Fitting of the cost function can be carried out by linear regression, Gaussian process regression, support vector machine regression, Bayesian regression, or another suitable technique. Based on the fitting performance between the test results and the fitted representation of the cost function, additional tests can be conducted to improve the accuracy of the fitted representation. Once the fitted representation with a desired accuracy is achieved, a globally or locally optimized combination of input parameters is determined or predicted using the fitted representation, such as by locating extrema using a stochastic or a deterministic optimization technique. Examples of stochastic techniques include simulated annealing, Markov chain Monte Carlo (MCMC), genetic optimization, differential evolution, and Gur game, among others. Examples of deterministic techniques include steepest descent and conjugate gradient, among others. An optimized combination of input parameters predicted from a fitted representation can be experimentally verified, such as by applying the optimized combination in vitro, in vivo, or in clinical/human tests.
[0089] Once a fitted representation with a desired accuracy is achieved for some embodiments, the significance of each input parameter and its synergistic effect with other input parameters can be identified. Non-significant input parameters that have little or no impact in affecting a state of a complex system can be dropped or omitted from an initial pool of input parameters, thereby effectively converting an initial multi-dimensional system to a refined system with a lower dimensionality. Taking the case of combinatorial drugs, for example, non-significant drugs can be identified as having low or negative values of the constants ?,·, βα, and β^, and can be dropped from an initial pool of drugs for subsequent evaluation.
EXAMPLES
[0090] The following examples describe specific aspects of some embodiments of this disclosure to illustrate and provide a description for those of ordinary skill in the art. The examples should not be construed as limiting this disclosure, as the example merely provides specific methodology useful in understanding and practicing some embodiments of this disclosure.
Example 1: Projected Inhibition
[0091] Experiments use anM tuberculosis Erdman inducible GFPuv strain (Mtb-iGFP) to infect human macrophages. Monolayers of differentiated TFIP-1 cells (from a human monocytic cell line) are infected with Mtb-iGFP prior to incubating in medium with isopropyl β-D-l-thiogalactopyranoside (IPTG) and TB drug combinations.
[0092] A pool of 15 drugs are evaluated, including the First-line drugs, Second-line Drugs, and Experimental TB drugs as follows:
1. First Line: Isoniazid (INH), Rifampin (RIF), Pyrazinamide (PZA), Ethambutol (EMB)
2. Second Line: Moxifloxacin (MXF), Para-amino-salicylic acid (PAS), Prothionamide (PRO), Cycloserine (CYC)
3. Experimental: Amoxicillin/Clavulanic Acid (A/C), Bedaquiline (BDQ), Clofazimine (CFZ), Linezolid (LNZ), PA824, SQ109, Delamanid (OPC-67683).
[0093] Drug combinations are determined by experimental design methodology according to the PRS scheme. Monolayers are imaged with a high throughput
epifluorescence microscope (see Example 2), and the inhibition is calculated by the following equation:
Inhibition =
Figure imgf000030_0001
:)
[0094] The results obtained are used to fit a quadratic model following the PRS scheme. Using this model, the following drug-dose combinations are identified as achieving > 60% projected TB inhibition:
Table 3: PRS-projected inhibition of 3- and 4-drug combinations.
Inhibition
1 Ethambutol PA824 Rifampicin OPC 1.08383258
2 A/C Ethambutol Rifampicin OPC 1.0638366
3 Clofazimine Ethambutol Rifampicin OPC 1.03269067
4 A/C Ethambutol PA824 Rifampicin 1.00955867
5 Clofazimine Ethambutol PA824 Rifampicin 1.00757849
6 A/C Clofazimine Ethambutol Rifampicin 1.00017004
7 Ethambutol ifampicin Bedaquiline OPC 0.99477134 Ethambutol PA824 Rifampicin Bedaquiline 0.97958984
Clofazimine PA824 Rifampicin OPC 0.97545285
PA824 ifampicin SQ109 OPC 0.97378558
A/C PA824 Rifampicin OPC 0.97203032
A/C Ethambutol Rifampicin Bedaquiline 0.95959386
Ethambutol Rifampicin OPC 0.95506676
Clofazimine PA824 SQ109 OPC 0.95200454
Clofazimine Ethambutol Pyrazinamide Rifampicin 0.94953013
A/C Ethambutol Pyrazinamide Rifampicin 0.94802861
Ethambutol Pyrazinamide Rifampicin OPC 0.94314282
PA824 Rifampicin Bedaquiline OPC 0.9420615
Ethambutol PA824 Rifampicin 0.93988526
Clofazimine Ethambutol PA824 OPC 0.93048751
Clofazimine Ethambutol Rifampicin Bedaquiline 0.92669177
Ethambutol PA824 Rifampicin SQ109 0.92326709
A/C Ethambutol PA824 OPC 0.92184934
Clofazimine Ethambutol Rifampicin 0.92139079
A/C Ethambutol Rifampicin 0.91988928
A/C Clofazimine Rifampicin OPC 0.91555358
PA824 Pyrazinamide Rifampicin OPC 0.91323692
Clofazimine Pyrazinamide SQ109 OPC 0.91073611
Clofazimine Pyrazinamide Rifampicin OPC 0.90941366
A/C Clofazimine Ethambutol OPC 0.90900412
Clofazimine Rifampicin SQ109 OPC 0.908203
Ethambutol PA824 Pyrazinamide Rifampicin 0.90626527
Clofazimine Ethambutol Rifampicin SQ109 0.90477263
A/C Pyrazinamide Rifampicin OPC 0.90250945
PA824 Rifampicin OPC 0.90235691
Clofazimine PA824 Pyrazinamide SQ109 0.89404837
A/C Clofazimine PA824 OPC 0.89278474
Ethambutol Rifampicin SQ109 OPC 0.89088697
Clofazimine PA824 Rifampicin SQ109 0.88905766
A/C Rifampicin SQ109 OPC 0.88634685
A/C Clofazimine Pyrazinamide OPC 0.88604478
Clofazimine PA824 Pyrazinamide OPC 0.88537425
A/C Clofazimine Ethambutol PA824 0.8790927
Ethambutol Pyrazinamide Rifampicin Bedaquiline 0.87896335
A/C Clofazimine Ethambutol Pyrazinamide 0.87476798
A/C Rifampicin Bedaquiline OPC 0.8695747
Pyrazinamide Rifampicin SQ109 OPC 0.86516827
Ethambutol PA824 Bedaquiline OPC 0.86376753
Clofazimine Pyrazinamide Rifampicin SQ109 0.86308175
A/C Ethambutol Rifampicin SQ109 0.86073777
A/C Clofazimine Pyrazinamide SQ109 0.85218556
Ethambutol Rifampicin Bedaquiline 0.85082402
A/C Clofazimine SQ109 OPC 0.8483824 Clofazimine Ethambutol PA824 SQ109 0.84469007
Clofazimine Ethambutol Pyrazinamide OPC 0.84426122
Clofazimine Rifampicin Bedaquiline OPC 0.84207531
Ethambutol Pyrazinamide Rifampicin 0.83925877
Clofazimine Rifampicin OPC 0.83677433
A/C PA824 SQ.109 OPC 0.83640055
PA824 Pyrazinamide Rifampicin SQ109 0.83425757
Ethambutol Rifampicin SQ109 Bedaquiline 0.83420585
Pyrazinamide Rifampicin Bedaquiline OPC 0.83344418 ifampicin SQ109 Bedaquiline OPC 0.83223352
Clofazimine PA824 Bedaquiline OPC 0.83028992
A/C Rifampicin OPC 0.82987012
A/C Ethambutol Bedaquiline OPC 0.8295917
PA824 Rifampicin SQ109 Bedaquiline 0.82301887
A/C Clofazimine Pyrazinamide Rifampicin 0.8228707
Ethambutol Pyrazinamide Rifampicin SQ109 0.8226406
Clofazimine Ethambutol PA824 Pyrazinamide 0.82160663
Clofazimine PA824 Pyrazinamide Rifampicin 0.82101065
PA824 SQ.109 Bedaquiline OPC 0.82085208
A/C PA824 Bedaquiline OPC 0.81800522
Clofazimine Ethambutol PA824 Bedaquiline 0.81659788
PA824 Pyrazinamide SQ109 OPC 0.81515048
A/C Clofazimine PA824 SQ109 0.81429427
Clofazimine PA824 OPC 0.81344432
A/C PA824 Pyrazinamide OPC 0.81230361
Clofazimine Ethambutol Pyrazinamide SQ109 0.81141247
A/C PA824 Rifampicin SQ109 0.81045435
A/C Clofazimine PA824 Rifampicin 0.80975018
A/C Ethambutol PA824 Bedaquiline 0.80971588
Clofazimine Ethambutol Bedaquiline OPC 0.80730795
A/C Ethambutol Pyrazinamide OPC 0.80108615
Clofazimine Ethambutol SQ109 OPC 0.798087
Clofazimine Ethambutol OPC 0.79513523
A/C Clofazimine Ethambutol Bedaquiline 0.79500958
Ethambutol Rifampicin SQ109 0.79450127
Clofazimine Ethambutol PA824 0.79417669
Pyrazinamide Rifampicin OPC 0.7937396
A/C Clofazimine Ethambutol SQ109 0.79355876
Rifampicin SQ.109 OPC 0.79252894
Clofazimine PA824 SQ109 Bedaquiline 0.78977857
Ethambutol PA824 SQ109 OPC 0.78908775
Clofazimine Pyrazinamide SQ109 Bedaquiline 0.78857342
A/C Clofazimine Rifampicin SQ109 0.78662505
Ethambutol PA824 OPC 0.78613599
A/C Clofazimine Ethambutol 0.78557871
A/C PA824 Pyrazinamide Rifampicin 0.78494069 100 Clofazimine SQ109 Bedaquiline OPC 0.78477026
101 PA824 Rifampicin SQ109 0.78331429
102 A/C Clofazimine PA824 Pyrazinamide 0.78269898
103 Clofazimine PA824 SQ109 0.78205516
104 A/C Pyrazinamide Rifampicin SQ109 0.78099675
105 Clofazimine Pyrazinamide SQ109 0.78085001
106 Clofazimine Pyrazinamide Bedaquiline OPC 0.7798993
107 Clofazimine SQ109 OPC 0.77704686
108 A/C Rifampicin SQ109 Bedaquiline 0.77697664
109 Clofazimine PA824 Rifampicin Bedaquiline 0.77536835
110 A/C PA824 Rifampicin Bedaquiline 0.77370199
111 Ethambutol PA824 Pyrazinamide OPC 0.77350266
112 Clofazimine Pyrazinamide OPC 0.77217589
113 Clofazimine PA824 Rifampicin 0.77006737
114 Clofazimine Ethambutol Pyrazinamide Bedaquiline 0.76862249
115 A/C PA824 SQ109 Bedaquiline 0.76755543
116 Clofazimine Ethambutol Pyrazinamide 0.76089909
117 ifampicin Bedaquiline OPC 0.76080485
118 A/C Clofazimine Bedaquiline OPC 0.76007893
119 A/C Ethambutol PA824 Pyrazinamide 0.75951428
120 Clofazimine Rifampicin SQ109 Bedaquiline 0.75568012
121 PA824 Pyrazinamide Rifampicin Bedaquiline 0.75497186
122 Pyrazinamide Rifampicin SQ109 Bedaquiline 0.75446483
123 PA824 Pyrazinamide Bedaquiline OPC 0.7542218
124 A/C Clofazimine OPC 0.75235552
125 A/C Ethambutol OPC 0.75196016
126 A/C Rifampicin SQ109 0.75135082
127 Clofazimine Rifampicin SQ109 0.75037914
128 Clofazimine Pyrazinamide Rifampicin Bedaquiline 0.74939243
129 A/C Pyrazinamide SQ109 OPC 0.74770981
130 A/C Pyrazinamide Rifampicin Bedaquiline 0.74424438
131 Clofazimine Pyrazinamide Rifampicin 0.74409146
132 PA824 SQ109 OPC 0.74322054
133 A/C PA824 OPC 0.74037368
134 A/C Ethambutol PA824 SQ109 0.74006438
135 A/C PA824 Rifampicin 0.73399741
136 A/C Ethambutol PA824 0.73208434
137 Clofazimine Ethambutol SQ109 Bedaquiline 0.72994662
138 A/C Pyrazinamide Bedaquiline OPC 0.72931447
139 A/C Ethambutol Pyrazinamide Bedaquiline 0.72901596
140 Ethambutol PA824 SQ109 Bedaquiline 0.72451591
141 Clofazimine Ethambutol SQ109 0.72222321
142 A/C Clofazimine Pyrazinamide Bedaquiline 0.71632046
143 Clofazimine PA824 Pyrazinamide Bedaquiline 0.71564994
144 A/C Clofazimine Rifampicin Bedaquiline 0.71546907
145 PA824 Pyrazinamide Rifampicin 0.71526728 146 Pyrazinamide Rifampicin SQ109 0.71476024
147 A/C Ethambutol SQ109 OPC 0.71237859
148 A/C PA824 Pyrazinamide SQ109 0.71210479
149 A/C Clofazimine Rifampicin 0.7101681
150 A/C Clofazimine Pyrazinamide 0.70859706
151 A/C SQ109 Bedaquiline 0.70849917
152 A/C SQ109 Bedaquiline OPC 0.70817633
153 Clofazimine PA824 Pyrazinamide 0.70792653
154 A/C Pyrazinamide Rifampicin 0.7045398
155 PA824 Rifampicin Bedaquiline 0.70402858
156 A/C Clofazimine SQ109 Bedaquiline 0.70399517
157 Ethambutol Pyrazinamide Bedaquiline OPC 0.7039079
158 Ethambutol PA824 Pyrazinamide Bedaquiline 0.70143247
159 PA824 Pyrazinamide SQ109 Bedaquiline 0.69655632
160 PA824 SQ109 Bedaquiline 0.69561003
161 Pyrazinamide SQ109 Bedaquiline OPC 0.6930649
162 A/C Clofazimine PA824 Bedaquiline 0.68480951
163 PA824 Bedaquiline OPC 0.68229186
164 Clofazimine Ethambutol Bedaquiline 0.67943323
165 A/C Clofazimine SQ109 0.67843302
166 PA824 Pyrazinamide OPC 0.67659026
167 Ethambutol PA824 Pyrazinamide SQ109 0.67431431
168 ifampicin SQ109 Bedaquiline 0.6742477
169 Ethambutol PA824 Bedaquiline 0.67400252
170 A/C Clofazimine PA824 0.67070577
171 A/C Ethambutol Pyrazinamide SQ109 0.65936446
172 Ethambutol SQ109 Bedaquiline OPC 0.65773368
173 Ethambutol Bedaquiline OPC 0.65478191
174 A/C Pyrazinamide OPC 0.65168293
175 A/C Ethambutol Pyrazinamide 0.65138442
176 A/C Ethambutol SQ109 Bedaquiline 0.64780674
177 Ethambutol PA824 SQ109 0.64688437
178 Clofazimine Bedaquiline OPC 0.64621004
179 A/C PA824 Pyrazinamide Bedaquiline 0.64614783
180 A/C Ethambutol Bedaquiline 0.6398267
181 Clofazimine SQ109 Bedaquiline 0.6397815
182 Clofazimine Rifampicin Bedaquiline 0.63668983
183 Pyrazinamide Rifampicin Bedaquiline 0.63547454
184 A/C Rifampicin Bedaquiline 0.63154178
185 A/C Bedaquiline OPC 0.63081559
186 Ethambutol Pyrazinamide SQ109 OPC 0.62922813
187 A/C Pyrazinamide SQ109 Bedaquiline 0.62911565
188 Ethambutol Pyrazinamide OPC 0.62627636
189 Ethambutol PA824 Pyrazinamide 0.62380093
190 A/C PA824 SQ109 0.62149162
191 PA824 Pyrazinamide SQ109 0.61892478 192 Pyrazinamide SQ.109 OPC 0.61543336
193 A/C SQ.109 OPC 0.61402055
194 Ethambutol Pyrazinamide SQ.109 Bedaquiline 0.60471956
195 Clofazimine PA824 Bedaquiline 0.60365673
196 Clofazimine Pyrazinamide Bedaquiline 0.60245157
[0095] Table 4 tabulates the drug-dose combinations with their respective calculated inhibition.
Table 4: PRS-projected inhibition of 3- and 4-drug, drug dose combinations (including doses).
1 = A/C, 2 = Clofazimine, 3 = Ethambutol, 4 = PA824, 5 = Pyrazinamide, 6 = Rifampicin, 7 = SQ109, 8 = Bedaquiline, 9 = OPC
Figure imgf000035_0001
0.127 0 0.0032 0 0 0.217 0 0.001 95.20%
0.127 0.2 0 0 0.016 0 0 0.001 95.09%
0.0625 0.2 0 22 0.016 0 0 0 94.95%
0 0.2 0 22 0.016 0 0 0 94.80%
0 0.2 0.0016 0 0.016 0 0 0.0005 94.75%
0 0.1 0 0 0.016 0 0 0.001 94.69%
0 0.2 0 22 0.016 0 0 0.001 94.31%
0 0 0.0032 0 0.016 0 0.007 0.001 94.21%
0 0.2 0.0032 0 0.016 0 0 0 93.99%
0 0.2 0 0 0.016 0 0.0035 0 93.97%
0 0.2 0 0 0.016 0 0 0.0005 93.75%
0 0 0.0032 0 0.016 0 0 0.001 93.72%
0 0.2 0.0032 0 0.008 0 0 0.001 93.50%
0.0625 0.1 0 0 0.016 0 0 0.001 93.47%
0.0625 0.2 0.0032 0 0 0 0 0.001 93.05%
0.0625 0.2 0 0 0.016 0 0.007 0 92.67%
0.0625 0 0.0032 0 0 0.217 0 0.001 92.56%
0.0625 0.2 0 0 0.016 0 0.0035 0 92.40%
0 0.2 0.0032 0 0.016 0.217 0 0 92.33%
0 0.2 0 0 0.016 0 0.007 0.0005 92.28%
0 0 0.0032 0 0.016 0 0.0035 0.001 92.22%
0 0.2 0.0032 0 0 0 0 0.001 92.18%
0.0625 0.2 0 0 0.016 0 0 0 92.14%
0.127 0.2 0 0 0.016 0 0 0 92.12%
0 0.2 0.0016 0 0.016 0 0 0 92.01%
0 0.2 0 0 0.016 0 0 0 91.99%
0.127 0.2 0.0032 0 0 0 0 0.001 91.76%
0 0.1 0.0016 0 0.016 0 0 0.001 91.56%
0.127 0.2 0.0032 0 0.016 0 0 0 91.56%
0.0625 0 0 0 0.016 0 0 0.001 91.56%
0 0.2 0.0016 0 0.016 0 0.007 0 91.52%
0 0 0.0032 22 0.016 0 0 0.001 91.32%
0.127 0.2 0 0 0.016 0 0 0.0005 91.21%
0.127 0 0 22 0 0.217 0 0.001 91.07%
0.0625 0 0 22 0.016 0 0 0.001 90.94%
0.127 0.2 0 0 0 0 0 0.001 90.90%
0.0625 0.2 0 0 0 0 0 0.001 90.89%
0.0625 0 0 0 0.016 0.217 0 0.001 90.82%
0 0.2 0 0 0.008 0 0 0.001 90.79%
0 0.2 0.0032 22 0.016 0 0 0 90.63%
0.0625 0 0.0016 0 0.016 0 0 0.001 90.61%
0 0.2 0 0 0.016 0 0.007 0 90.52%
0.0625 0.2 0 0 0.016 0.217 0 0 90.48%
0 0.2 0 0 0.016 0 0.0035 0.0005 90.29% 0 0 0 22 0.016 0 0 0.001 90.25%
0 0 0.0032 0 0.016 0 0 0.001 90.24%
0.127 0.2 0 22 0.016 0 0 0 90.15%
0 0 0.0016 0 0.016 0 0 0.001 90.10%
0.0625 0.2 0 0 0.008 0 0 0.001 89.84%
0 0.1 0.0032 0 0.016 0 0 0.0005 89.76%
0.127 0.2 0 0 0.016 0 0 0 89.72%
0 0.2 0.0016 0 0.016 0 0.0035 0 89.54%
0.127 0.2 0.0016 0 0.016 0 0 0 89.45%
0.127 0 0.0032 22 0 0.217 0 0 89.40%
0 0.2 0 22 0.016 0 0 0 89.36%
0.0625 0 0.0032 0 0 0 0 0.001 89.28%
0 0.1 0 0 0.016 0 0 0.001 89.25%
0 0.2 0 22 0.016 0 0 0.0005 89.12%
0 0.2 0 0 0.016 0.217 0 0.001 89.09%
0.0625 0.2 0.0032 0 0.008 0 0 0 89.05%
0.0625 0 0.0032 0 0.016 0.217 0 0 88.91%
0.127 0 0.0032 0 0.016 0 0 0.001 88.90%
0.0625 0.1 0.0032 0 0.016 0 0 0 88.88%
0.127 0 0.0032 0 0 0 0 0.001 88.82%
0 0 0 0 0.00929 0.19254 0 0.00134 88.63%
0.127 0 0 22 0 0 0 0.001 88.60%
0.127 0 0.0032 22 0 0 0 0.001 88.54%
0 0.2 0 0 0.016 0 0.0035 0 88.54%
0 0 0.0016 0 0.016 0.217 0 0.001 88.32%
0 0.2 0 0 0.016 0 0 0.0005 88.31%
0.0625 0 0.0032 0 0.008 0 0 0.001 88.13%
0 0.2 0 11 0.016 0 0 0.001 87.93%
0.0625 0.2 0.0032 0 0 0 0 0 87.91%
0 0.2 0 22 0.016 0 0.007 0 87.90%
0 0 0.0032 0 0.016 0.217 0 0.0005 87.85%
0 0.1 0 0 0.016 0 0.007 0.001 87.78%
0.0625 0 0 0 0.016 0 0 0.001 87.62%
0.0625 0.2 0 0 0.008 0 0 0 87.60%
0 0.2 0.0016 0 0.016 0 0 0 87.55%
0.127 0.2 0 22 0 0 0 0 87.48%
0.127 0.2 0 0 0.016 0 0 0 87.33%
0.127 0.2 0 0 0.008 0 0 0.001 87.30%
0 0.2 0.0016 22 0.016 0 0 0 87.28%
0.0625 0 0.0032 0 0.016 0 0 0.0005 87.28%
0.127 0.1 0 0 0.016 0 0 0.001 87.26%
0 0.1 0.0032 0 0.016 0 0 0 87.18%
0 0.2 0.0032 0 0.008 0 0 0 87.08%
0 0 0 0 0.016 0 0.007 0.001 86.96% 0.127 0.2 0.0032 0 0 0 0 0 86.89%
0 0.1 0 22 0.016 0 0 0.001 86.84%
0.127 0 0.0032 0 0 0.217 0 0.0005 86.70%
0.127 0 0 22 0.016 0 0 0.001 86.69%
0.127 0 0 0 0.016 0.217 0 0.001 86.57%
0.0625 0.2 0 11 0.016 0 0 0 86.57%
0.127 0.1 0.0032 0 0 0 0 0.001 86.55%
0 0.2 0 0 0.016 0 0 0 86.55%
0 0 0 22 0.016 0.217 0 0.001 86.52%
0.127 0 0.0016 0 0 0.217 0 0.001 86.45%
0 0.2 0 11 0.016 0 0 0 86.42%
0 0.2 0.0032 0 0 0 0.007 0.001 86.38%
0.0625 0 0 22 0.016 0.217 0 0 86.31%
0 0.2 0 0 0.016 0.217 0 0 86.07%
0 0.2 0 22 0.016 0 0.0035 0 85.91%
0.0625 0 0.0032 22 0 0 0 0.001 85.90%
0 0.2 0.0016 0 0.016 0.217 0 0 85.89%
0.0625 0.1 0.0032 0 0 0 0 0.001 85.88%
0 0 0 0 0.016 0.217 0 0.001 85.88%
0 0 0.0032 0 0.008 0.217 0 0.001 85.85%
0.127 0.2 0 0 0.016 0 0.0035 0 85.82%
0 0.1 0 0 0.016 0 0.0035 0.001 85.79%
0.127 0.2 0 0 0.016 0.217 0 0 85.67%
0.127 0.2 0.0016 0 0 0 0 0.001 85.64%
0 0 0.0016 0 0.016 0 0 0.001 85.63%
0 0 0.0032 0 0.008 0 0 0.001 85.62%
0.127 0.2 0.0032 0 0 0 0 0.0005 85.59%
0.0625 0.1 0 0 0.016 0 0 0.0005 85.56%
0.0625 0.1 0 0 0.016 0 0 0 85.52%
0.127 0.2 0.0032 0 0.008 0 0 0 85.49%
0.127 0 0 22 0.016 0.217 0 0 85.43%
0 0.2 0.0032 0 0 0 0 0.001 85.40%
0 0 0.0016 22 0.016 0 0 0.001 85.35%
0.127 0.2 0 0 0.008 0 0 0 85.34%
0 0.2 0.0032 11 0.016 0 0 0 85.33%
0 0.1 0.0032 0 0.016 0.217 0 0 85.33%
0 0 0.0032 0 0.016 0 0 0.0005 85.30%
0.127 0 0 22 0 0.217 0 0 85.22%
0.127 0.2 0 0 0 0 0 0.001 85.21%
0.0625 0.2 0.0032 0 0 0 0 0.0005 85.19%
0 0.2 0.0032 0 0.008 0 0 0.0005 85.16%
0 0 0.0016 0 0.016 0 0.007 0.001 85.14%
0 0.1 0 0 0.016 0 0 0.0005 85.14%
0.127 0 0.0032 0 0.008 0 0 0.001 85.12% 0.127 0 0.0032 0 0 0 0 0.001 85.08%
0 0.2 0 0 0.016 0 0.007 0 85.08%
0 0.2 0.0016 0 0.008 0 0 0.001 85.05%
0 0 0 0 0.016 0 0.0035 0.001 84.97%
0.127 0 0 0 0 0.217 0 0.001 84.84%
0 0 0 22 0.016 0 0 0.001 84.81%
0.127 0.2 0 0 0 0 0 0.0005 84.73%
0.0625 0.2 0.0016 0 0 0 0 0.001 84.73%
0.0625 0.1 0 22 0.016 0 0 0 84.68%
0.0625 0 0 22 0 0 0 0.001 84.67%
0.127 0 0 22 0 0.217 0 0.0005 84.58%
0.127 0.2 0.0032 0 0 0.217 0 0 84.47%
0.127 0.2 0 22 0 0 0 0.001 84.43%
0 0.1 0.0032 0 0.008 0 0 0.001 84.42%
0.127 0.2 0 0 0.016 0 0.007 0 84.31%
0 0.2 0 0 0.016 0.217 0 0.0005 84.27%
0.127 0 0 0 0.016 0 0 0.001 84.21%
0.0625 0 0 0 0.016 0 0.007 0.001 84.21%
0 0.1 0.0032 0 0.016 0 0.007 0 84.18%
0 0.1 0 0 0.016 0.217 0 0.001 84.17%
0.127 0 0.0016 0 0.016 0 0 0.001 84.17%
0.0625 0.2 0 22 0 0 0 0 84.10%
0.0625 0 0 22 0 0.217 0 0.001 84.04%
0 0 0.0032 0 0.016 0.1085 0 0.001 84.02%
0.0625 0 0.0032 0 0 0 0 0.001 83.99%
0.0625 0 0 0 0.016 0 0.0035 0.001 83.94%
0 0.2 0 22 0.016 0 0 0 83.93%
0 0.1 0 0 0.016 0 0 0.001 83.81%
0 0 0.0032 11 0.016 0 0 0.001 83.80%
0.127 0 0.0016 22 0 0.217 0 0 83.74%
0 0 0.00261 0 0.00929 0 0 0.00134 83.70%
0 0.2 0 0 0.008 0 0 0.001 83.70%
0 0.1 0.0032 0 0.016 0 0 0 83.69%
0 0.2 0.0016 0 0 0 0 0.001 83.69%
0.0625 0 0 0 0.016 0 0 0.001 83.68%
0.0625 0.2 0 0 0 0 0 0.001 83.65%
0 0 0.0032 0 0 0.217 0 0.001 83.64%
0.127 0 0.0032 0 0.016 0.217 0 0 83.63%
0 0 0.0032 22 0.016 0.217 0 0 83.43%
0 0.2 0 0 0.016 0.217 0.007 0 83.42%
0.0625 0 0.0032 22 0 0.217 0 0 83.40%
0 0.2 0.0032 0 0.016 0.1085 0 0 83.37%
0 0 0 22 0.016 0 0.007 0.001 83.34%
0.0625 0.1 0.0016 0 0.016 0 0 0 83.26% 0 0 0 0 0.016 0.217 0.007 0.001 83.22%
0 0 0.0016 0 0.016 0 0.0035 0.001 83.16%
0.127 0.2 0.0032 0 0 0 0 0 83.16%
0.0625 0.2 0 0 0.008 0 0 0.0005 83.13%
0.127 0.2 0 22 0.008 0 0 0 83.12%
0 0.1 0.0032 0 0 0 0 0.001 83.11%
0 0 0.00261 0 0.00929 0.19254 0 0.00134 83.10%
0 0.2 0 0 0.016 0 0.0035 0 83.10%
0.127 0.1 0 0 0 0 0 0.001 83.07%
0.0625 0.2 0 0 0 0 0 0.0005 83.03%
0.0625 0 0.0032 0 0 0 0.007 0.001 83.03%
0 0 0 0 0.016 0 0 0.001 82.99%
0 0.2 0 0 0 0 0.007 0.001 82.96%
0.0625 0 0 0 0.016 0.217 0 0.0005 82.93%
0.127 0 0 22 0 0 0 0.001 82.91%
0.127 0 0.0016 22 0 0 0 0.001 82.88%
0 0.2 0 0 0.016 0.217 0 0 82.76%
0.0625 0.1 0 0 0.016 0.217 0 0 82.76%
0.0625 0.2 0.0016 0 0.008 0 0 0 82.73%
0.127 0.2 0.0016 0 0 0 0 0 82.73%
0 0.2 0.0032 0 0 0 0 0.0005 82.70%
0 0.2 0.0032 0 0.008 0 0.007 0 82.68%
0.0625 0 0 22 0.016 0 0 0.0005 82.68%
0 0.1 0 22 0.016 0 0 0 82.63%
0.0625 0.2 0.0032 0 0 0 0 0 82.62%
0 0 0 0 0.016 0.217 0 0.001 82.56%
0 0.2 0 0 0.016 0.1085 0 0.001 82.51%
0 0.2 0.0032 0 0 0 0.0035 0.001 82.50%
0 0.2 0 0 0.008 0 0.007 0.001 82.48%
0 0.2 0 0 0.008 0 0 0.0005 82.45%
0.0625 0.2 0.0032 0 0 0.217 0 0 82.39%
0.0625 0 0.0032 0 0 0.217 0 0.0005 82.38%
0 0 0.001305 0 0.00929 0 0 0.00134 82.32%
0 0 0.0032 0 0.016 0 0.007 0.0005 82.30%
0 0 0.0032 0 0.016 0.217 0.007 0 82.30%
0.0625 0 0 22 0.016 0 0 0 82.29%
0.0625 0.2 0 22 0.008 0 0 0 82.28%
0.127 0.2 0 0 0.008 0 0 0.0005 82.28%
0 0.2 0 22 0.016 0.217 0 0 82.26%
0 0.1 0.0032 0 0.016 0 0.0035 0 82.20%
0.127 0.2 0.0032 22 0 0 0 0 82.16%
0.127 0 0 0 0.008 0.217 0 0.001 82.14%
0.127 0 0.0032 0 0 0 0.007 0.001 82.12%
0.0625 0 0.0032 22 0.016 0 0 0 82.10% 0 0 0.0032 0 0 0.217 0.007 0.001 82.09%
0.127 0 0.0016 0 0 0 0 0.001 82.03%
0 0.1 0.0016 0 0.016 0 0 0.0005 82.01%
0.0625 0.2 0 0 0.008 0 0 0 82.01%
0.0625 0 0.0016 0 0.016 0.217 0 0 81.97%
0.127 0 0 22 0.008 0 0 0.001 81.96%
0 0.2 0.0032 0 0.008 0 0 0 81.95%
0 0 0 0 0.00929 0.19254 0 0.00067 81.88%
0.127 0.1 0 22 0.016 0 0 0 81.84%
0.127 0 0 0 0.016 0 0 0.001 81.82%
0 0 0.0032 0 0.016 0 0 0.0005 81.82%
0 0 0.0032 0 0 0 0.007 0.001 81.80%
0.127 0.2 0 22 0 0 0 0 81.78%
0.127 0.2 0 11 0.016 0 0 0 81.76%
0.127 0 0 22 0.008 0.217 0 0 81.76%
0 0.2 0 11 0.016 0 0 0.0005 81.74%
0.127 0 0.0032 0 0 0 0.0035 0.001 81.73%
0.0625 0.2 0.0032 0 0 0 0.007 0 81.66%
0.127 0 0 22 0 0.217 0 0 81.65%
0.127 0.1 0.0032 0 0.016 0 0 0 81.65%
0.0625 0 0.0016 0 0 0.217 0 0.001 81.62%
0.0625 0.1 0 0 0.016 0 0 0 81.58%
0.0625 0.2 0.0016 0 0 0 0 0 81.54%
0.0625 0.2 0 0 0.016 0.1085 0 0 81.52%
0 0 0 0 0.016 0 0.007 0.001 81.52%
0 0 0.0032 22 0 0.217 0 0.001 81.52%
0 0.2 0 0 0.016 0.217 0.0035 0 81.44%
0.127 0 0.0032 0 0 0.217 0 0 81.43%
0.0625 0 0 0 0.008 0 0 0.001 81.43%
0 0 0.0032 22 0.016 0 0 0.0005 81.43%
0 0.1 0.0016 0 0.016 0 0 0 81.38%
0.127 0.2 0.0016 0 0.008 0 0 0 81.37%
0 0 0 22 0.016 0 0.0035 0.001 81.36%
0.127 0 0.0032 0 0 0 0 0.001 81.34%
0.127 0.1 0.0032 0 0 0.217 0 0 81.34%
0.0625 0.2 0 22 0 0 0 0.001 81.32%
0.127 0.2 0 0 0.008 0 0 0 81.29%
0.0625 0 0 0 0.016 0 0 0.0005 81.29%
0.127 0 0 0 0 0.217 0 0.001 81.27%
0 0 0 0 0.016 0.217 0.0035 0.001 81.24%
0 0 0.0032 22 0 0 0 0.001 81.23%
0 0 0.0032 0 0.008 0 0.007 0.001 81.22%
0 0 0.0016 0 0.016 0 0 0.001 81.17%
0.127 0.2 0 22 0 0.217 0 0 81.14% 0.0625 0.1 0 0 0 0 0 0.001 81.09%
0 0.1 0.0032 22 0.016 0 0 0 81.08%
0 0 0.0032 0 0.016 0.217 0 0 81.05%
0.127 0.1 0 0 0.016 0 0 0.0005 81.03%
0 0.2 0 11 0.016 0 0 0 80.98%
0.0625 0 0.0032 0 0.016 0 0 0 80.98%
0 0.2 0.0032 0 0 0 0.007 0 80.97%
0 0 0 0 0.00929 0 0 0.00134 80.93%
0.127 0 0.0032 0 0.008 0.217 0 0 80.92%
0.0625 0 0 0 0 0.217 0 0.001 80.90%
0.0625 0 0.0032 0 0 0 0.0035 0.001 80.87%
0.127 0.1 0 22 0 0 0 0.001 80.82%
0.0625 0 0 0 0.008 0.217 0 0.001 80.75%
0.0625 0.2 0 0 0 0 0.007 0.001 80.73%
0 0 0 0 0.00929 0.19254 0 0.00134 80.67%
0 0.2 0.0016 0 0.008 0 0 0 80.59%
0.0625 0 0 22 0.008 0 0 0.001 80.56%
0.0625 0 0.0032 0 0.008 0.217 0 0 80.55%
0 0 0.0032 0 0.008 0 0 0.001 80.49%
0 0.2 0.0016 11 0.016 0 0 0 80.44%
0.127 0 0 0 0.016 0.217 0 0.0005 80.37%
0 0 0 22 0.016 0 0 0.0005 80.35%
0.0625 0 0.0016 0 0.016 0 0 0.0005 80.34%
0.0625 0 0 11 0.016 0 0 0.001 80.33%
0 0 0.0032 0 0.016 0 0.0035 0.0005 80.32%
0.127 0 0.0032 0 0.016 0 0 0.0005 80.32%
0 0 0.0032 0 0.016 0.217 0.0035 0 80.32%
0.0625 0 0.0016 0 0 0 0 0.001 80.29%
0.127 0.2 0 0 0 0 0.007 0.001 80.29%
0.127 0.2 0 22 0 0 0 0.0005 80.26%
0 0.1 0.0032 0 0.016 0 0 0 80.21%
0.127 0.2 0.0032 0 0 0 0.007 0 80.19%
0.127 0 0 22 0.016 0 0 0.0005 80.11%
0 0.2 0 22 0 0 0 0.001 80.11%
0.0625 0.2 0.0032 22 0 0 0 0 80.08%
0.0625 0.1 0 0 0.008 0 0 0.001 80.04%
0 0.2 0 0 0.008 0 0.007 0 79.97%
0 0.2 0 22 0.008 0 0 0 79.97%
0.127 0.1 0 0 0.016 0.217 0 0 79.92%
0.127 0.2 0 0 0 0 0.0035 0.001 79.90%
0.127 0 0.0032 0 0 0.217 0 0 79.82%
0.127 0.2 0 0 0 0.217 0 0.001 79.81%
0.127 0.2 0.0032 0 0 0 0.0035 0 79.80%
0 0.2 0.0032 0 0.008 0 0.0035 0 79.75% 0.127 0 0 22 0 0 0 0.0005 79.73%
0.127 0 0 0 0.008 0 0 0.001 79.72%
0 0.1 0 0 0.016 0 0 0.0005 79.70%
0 0 0.0032 0 0.016 0.217 0 0 79.69%
0.127 0 0.0032 22 0 0 0 0.0005 79.67%
0 0 0 11 0.016 0 0 0.001 79.64%
0.127 0.1 0 22 0 0.217 0 0 79.61%
0.127 0.1 0 0 0.016 0 0 0 79.58%
0 0.1 0 0 0.016 0 0.007 0 79.56%
0 0.2 0 0 0.008 0 0.0035 0.001 79.54%
0 0 0 0 0.016 0 0.0035 0.001 79.53%
0.127 0.2 0 0 0 0 0 0.001 79.51%
0 0.2 0 11 0.016 0 0.007 0 79.51%
0.0625 0.2 0 0 0 0 0.007 0 79.50%
0.0625 0.2 0.0032 0 0 0 0.0035 0 79.50%
0 0 0.0032 22 0.008 0 0 0.001 79.49%
0.127 0.1 0 0 0.008 0 0 0.001 79.47%
0.127 0.2 0.0016 0 0 0 0 0.0005 79.47%
0 0.2 0 0 0.016 0.217 0 0 79.45%
0.127 0 0 0 0.016 0 0 0.001 79.43%
0.127 0.2 0.0032 0 0 0 0 0 79.42%
0 0 0 22 0.016 0 0 0.001 79.37%
0.127 0.2 0 0 0 0.217 0 0 79.36%
0.127 0.2 0 0 0 0 0.007 0 79.33%
0 0.1 0 22 0.016 0 0 0.0005 79.30%
0 0 0 0 0.016 0.217 0 0.001 79.25%
0 0.2 0 0 0.016 0.1085 0 0 79.25%
0.0625 0 0.0016 0 0.008 0 0 0.001 79.19%
0.127 0.1 0 22 0 0 0 0 79.17%
0.127 0.2 0.0016 22 0 0 0 0 79.13%
0.127 0.1 0.0016 0 0 0 0 0.001 79.12%
0 0.1 0 0 0.008 0 0 0.001 79.09%
0 0.2 0 0 0 0 0.0035 0.001 79.08%
0.127 0.2 0 0 0 0 0 0.0005 79.04%
0 0 0 22 0.016 0.217 0 0.0005 79.00%
0.0625 0 0.0032 0 0.016 0 0 0 78.99%
0 0 0.0032 0 0 0.217 0 0.001 78.98%
0.127 0 0.0032 0 0 0.217 0.007 0 78.98%
0.127 0.2 0 0 0.008 0.217 0 0 78.95%
0.127 0.2 0 0 0 0 0.0035 0 78.94%
0 0.2 0.0032 0 0 0.217 0 0.001 78.91%
0.127 0 0.0016 0 0.016 0.217 0 0 78.90%
0.127 0 0 22 0 0.217 0.007 0 78.86%
0.0625 0.2 0 0 0.008 0 0.007 0 78.84% 0 0 0.0016 0 0.016 0.217 0 0.0005 78.79%
0.127 0.1 0 0 0 0.217 0 0.001 78.76%
0.0625 0 0.0032 0 0 0 0 0.001 78.71%
0.0625 0 0 0 0.016 0.217 0 0 78.66%
0 0.2 0.0032 0 0 0 0 0.001 78.61%
0.127 0 0.0032 0 0 0.217 0.0035 0 78.59%
0.0625 0.2 0 0 0 0 0.0035 0.001 78.57%
0.127 0.2 0 0 0 0 0 0 78.56%
0.0625 0 0.0032 0 0 0.217 0 0 78.52%
0 0.2 0.0032 0 0.008 0.217 0 0 78.51%
0 0 0.0032 22 0.016 0 0 0 78.49%
0.127 0 0.0032 0 0 0.1085 0 0.001 78.49%
0.127 0 0 0 0 0.217 0.007 0.001 78.48%
0.127 0 0 22 0 0.217 0.0035 0 78.47%
0 0.2 0 22 0.008 0 0 0.001 78.47%
0.127 0 0.0016 0 0.008 0 0 0.001 78.38%
0.0625 0 0 22 0.016 0 0 0 78.35%
0 0.1 0 11 0.016 0 0 0.001 78.35%
0.127 0.2 0.0016 0 0 0.217 0 0 78.35%
0 0 0.0032 0 0.016 0 0 0.0005 78.33%
0 0 0.0032 0 0.016 0.217 0 0 78.33%
0.127 0 0 22 0.016 0 0 0 78.31%
0 0 0.0032 0 0.008 0 0.0035 0.001 78.28%
0.127 0 0.0032 22 0 0 0 0 78.27%
0.0625 0 0.0016 22 0.016 0 0 0 78.26%
0 0.1 0 0 0.016 0 0.007 0.0005 78.23%
0.127 0.1 0.0016 0 0.016 0 0 0 78.22%
0.127 0 0.0032 0 0 0.217 0 0 78.21%
0 0 0.0032 0 0 0.217 0.0035 0.001 78.20%
0 0 0.0016 0 0.016 0 0 0.0005 78.19%
0.0625 0.1 0 0 0.016 0 0.007 0 78.17%
0.0625 0.2 0 0 0.008 0.217 0 0 78.11%
0 0 0 0 0.00929 0.09627 0 0.00134 78.10%
0 0 0 22 0.016 0.217 0 0 78.10%
0.127 0 0 0 0 0.217 0.0035 0.001 78.09%
0.127 0 0 22 0 0.217 0 0 78.09%
0.0625 0 0.0016 22 0 0 0 0.001 78.04%
0.127 0.1 0.0032 0 0 0 0 0.0005 78.03%
0.127 0.2 0.0016 0 0 0 0 0 78.01%
0.127 0 0 22 0 0 0.007 0.001 77.99%
0.127 0 0.0032 11 0 0 0 0.001 77.96%
0.127 0 0.0016 0 0 0.217 0 0.0005 77.96%
0.127 0 0.0032 0 0 0 0 0.0005 77.95%
0.127 0 0 0 0.016 0 0.0035 0.001 77.92% 0 0 0.0032 0 0 0 0.0035 0.001 77.92%
0.0625 0 0 22 0 0.217 0 0 77.91%
0 0 0.00261 0 0.00929 0.19254 0 0 77.91%
0.0625 0.1 0 0 0.016 0 0.0035 0 77.90%
0 0 0.001305 0 0.00929 0.19254 0 0.00134 77.90%
0 0 0 22 0.008 0 0 0.001 77.71%
0.127 0 0 0 0 0.217 0 0.001 77.70%
0 0 0 0 0.00929 0.19254 0.01076 0 77.70%
0.0625 0.1 0 0 0.016 0 0 0 77.64%
0.0625 0.2 0 0 0.008 0 0.0035 0 77.63%
0.127 0 0 22 0 0 0.0035 0.001 77.60%
0 0.1 0.0016 0 0.016 0.217 0 0 77.58%
0 0.1 0 0 0.016 0 0.0035 0 77.57%
0 0 0 0 0.016 0 0 0.001 77.55%
0.0625 0 0.0032 0 0.016 0 0.007 0 77.54%
0 0.2 0 11 0.016 0 0.0035 0 77.53%
0.051 0 0.00261 0 0 0.19254 0.01076 0 77.51%
0.0625 0 0 0 0.016 0.1085 0 0.001 77.46%
0 0 0.0016 22 0.016 0.217 0 0 77.45%
0.0625 0 0 22 0 0 0 0.001 77.43%
0.127 0 0 11 0 0.217 0 0.001 77.41%
0.127 0.1 0 0 0 0 0 0.001 77.37%
0 0 0.0032 0 0.016 0 0.007 0 77.37%
0 0.2 0.0032 22 0 0 0 0.001 77.35%
0.0625 0 0 0 0.016 0 0 0.0005 77.35%
0.0625 0.2 0 0 0 0 0.0035 0 77.34%
0.0625 0.2 0.0032 0 0 0 0 0 77.34%
0.127 0 0.0016 0 0 0 0 0.001 77.31%
0 0.1 0.0032 0 0 0 0.007 0.001 77.30%
0.0625 0.1 0.0032 0 0 0.217 0 0 77.29%
0.0625 0 0.0032 0 0.016 0 0.0035 0 77.27%
0.127 0.2 0 0 0.008 0 0 0 77.25%
0.127 0 0 22 0 0 0 0.001 77.22%
0 0.1 0 22 0.016 0 0 0 77.19%
0.127 0.1 0 0 0.016 0 0 0 77.19%
0.0625 0.1 0.0032 0 0.008 0 0 0 77.17%
0 0.2 0.0032 0 0 0 0.0035 0 77.09%
0 0.2 0 0 0.008 0 0.0035 0 77.04%
0.0625 0 0.0032 0 0.016 0 0 0 77.01%
0 0.1 0 0 0.016 0.217 0 0.0005 77.00%
0.0625 0 0 22 0.008 0.217 0 0 77.00%
0.127 0.1 0.0032 0 0 0 0 0 76.98%
0 0.2 0.0016 0 0.016 0.1085 0 0 76.94%
0 0.1 0.0016 0 0.016 0 0 0 76.92% 0 0.2 0.0032 0 0 0 0.007 0.0005 76.89%
0.0625 0.2 0.0016 0 0 0 0 0.0005 76.87%
0 0.1 0 22 0.016 0.217 0 0 76.87%
0.127 0.2 0 22 0 0 0.007 0 76.86%
0.0625 0.2 0 22 0 0 0 0 76.86%
0.0625 0 0 0 0.016 0.217 0 0 76.85%
0.127 0 0.0032 22 0.016 0 0 0 76.83%
0.127 0 0.0032 11 0 0.217 0 0 76.83%
0 0.2 0.0032 0 0.008 0 0 0 76.81%
0 0 0.00261 0 0 0.19254 0.01076 0 76.76%
0.127 0.2 0 0 0.016 0.1085 0 0 76.72%
0.0625 0 0.0032 0 0 0 0 0.0005 76.72%
0 0.2 0.0016 0 0.008 0 0 0.0005 76.71%
0.0625 0 0.0032 0 0.008 0 0 0.0005 76.71%
0.0625 0.2 0 0 0 0.217 0 0.001 76.70%
0.127 0.2 0 0 0.008 0 0.0035 0 76.69%
0 0.1 0.0032 0 0 0.217 0 0.001 76.62%
0 0.2 0 0 0.008 0 0 0.001 76.61%
0 0 0.001305 0 0.00929 0.19254 0 0 76.52%
0.0625 0 0.0032 0 0 0.217 0.007 0 76.52%
0 0 0.0016 0 0.008 0 0 0.001 76.51%
0 0.2 0 0 0.016 0.1085 0 0.0005 76.51%
0 0.2 0.0032 22 0.008 0 0 0 76.50%
0.127 0.1 0.0032 22 0 0 0 0 76.48%
0.127 0.2 0 22 0 0 0.0035 0 76.48%
0 0.1 0 0 0.016 0.217 0 0 76.45%
0 0.1 0.0016 0 0.016 0 0.007 0 76.43%
0.0625 0.2 0 0 0.008 0 0 0 76.42%
0 0.1 0.0016 22 0.016 0 0 0 76.41%
0.127 0 0 0 0.016 0 0.007 0.001 76.41%
0.0625 0.2 0 0 0 0 0 0.001 76.41%
0.0255 0 0 0 0.00929 0 0 0.00134 76.38%
0 0 0 0 0.016 0.217 0 0.0005 76.35%
0 0 0.00261 0 0.00929 0.19254 0 0.00067 76.35%
0.127 0 0 0 0 0.217 0 0.0005 76.34%
0 0.1 0.0032 0 0 0 0 0.001 76.33%
0 0 0.0016 11 0.016 0 0 0.001 76.28%
0.0625 0.1 0.0016 0 0 0 0 0.001 76.24%
0 0.1 0 0 0.016 0 0.0035 0.0005 76.24%
0 0 0.00261 0 0.00929 0 0 0.00134 76.21%
0.127 0.2 0 0 0.008 0 0.007 0 76.13%
0.127 0.2 0 22 0 0 0 0 76.09%
0.127 0 0 11 0.016 0 0 0.001 76.08%
0 0 0 0 0.016 0 0.007 0.001 76.08% 0.127 0.2 0 11 0 0 0 0 76.04%
0.0625 0.1 0.0032 0 0 0 0 0 76.03%
0.127 0.2 0 0 0 0.217 0 0.0005 76.02%
0.127 0 0 0 0 0 0.007 0.001 76.01%
0.0625 0 0.0016 0 0.016 0 0 0 76.00%
0.0625 0.2 0 0 0 0.217 0 0 75.98%
0 0.2 0.0032 22 0 0 0 0 75.95%
0 0.2 0.0016 0 0 0 0.007 0.001 75.93%
0 0.2 0.0016 0 0 0 0 0.001 75.93%
0.127 0 0 22 0.016 0 0 0 75.92%
0 0.2 0.0032 0 0 0 0 0.0005 75.91%
0 0 0 11 0.016 0.217 0 0.001 75.91%
0.0625 0 0 22 0 0.217 0 0.0005 75.86%
0.0625 0 0.0032 0 0 0.1085 0 0.001 75.85%
0.0625 0 0 0 0.008 0 0 0.001 75.84%
0.0625 0.2 0 0 0 0 0 0.0005 75.79%
0.127 0.2 0 0 0 0.217 0 0 75.79%
0.0625 0 0 0 0 0.217 0 0.001 75.79%
0.0625 0.1 0 22 0 0 0 0.001 75.75%
0 0.1 0 22 0.016 0 0.007 0 75.72%
0.127 0 0 0 0.008 0 0 0.001 75.68%
0.0625 0.1 0.0032 0 0 0 0 0.0005 75.67%
0.127 0 0 0 0.016 0 0 0.0005 75.63%
0.127 0 0 0 0 0 0.0035 0.001 75.62%
0.0625 0 0 0 0 0 0.007 0.001 75.62%
0 0.1 0 0 0.016 0 0 0 75.59%
0.127 0 0.0016 0 0.016 0 0 0.0005 75.58%
0.127 0.1 0.0032 0 0.008 0 0 0 75.58%
0.0625 0 0 0 0.016 0.217 0.007 0 75.57%
0 0.2 0 11 0.016 0 0 0 75.54%
0.0625 0 0.0016 22 0 0.217 0 0 75.54%
0 0 0.0032 22 0.016 0 0.007 0 75.50%
0.0625 0.2 0 22 0 0 0 0.0005 75.47%
0 0 0.0016 22 0.016 0 0 0.0005 75.45%
0 0 0 22 0.016 0.217 0.007 0 75.45%
0 0 0.0032 22 0 0 0.007 0.001 75.42%
0.127 0 0.0032 0 0.008 0 0 0.0005 75.39%
0 0 0.0032 0 0.016 0 0.0035 0 75.38%
0 0.2 0 0 0.008 0 0 0.0005 75.36%
0.0625 0 0.0032 0 0 0.217 0 0 75.36%
0.0625 0 0.0032 22 0 0 0 0 75.36%
0 0 0.0032 0 0.008 0 0 0.001 75.35%
0.0625 0 0.0032 22 0 0 0 0.0005 75.34%
0.0625 0 0.0032 11 0 0 0 0.001 75.32% 0.0625 0 0 0 0.016 0.217 0.0035 0 75.30%
0.0625 0.2 0.0016 0 0 0 0 0 75.28%
0.127 0 0 0 0 0 0 0.001 75.24%
0 0.2 0 0 0 0 0 0.001 75.20%
0 0 0.0032 0 0.008 0.217 0 0.0005 75.18%
0.127 0 0.0016 22 0.016 0 0 0 75.18%
0.0625 0.2 0 0 0 0 0 0 75.18%
0 0 0 0 0.00929 0.19254 0 0 75.14%
0 0 0 0 0.016 0 0.007 0.0005 75.06%
0.0625 0 0 0 0.016 0.217 0 0 75.04%
0 0 0.0032 0 0 0 0.007 0.001 75.01%
0 0 0.0032 22 0.016 0 0 0 75.01%
0.0625 0 0 0 0 0.217 0.007 0.001 75.00%
0.127 0.2 0 11 0 0 0 0.001 74.99%
0 0 0.0016 0 0.016 0.1085 0 0.001 74.96%
0.127 0 0 11 0 0 0 0.001 74.94%
0.0625 0 0 22 0.016 0 0.007 0 74.94%
0 0 0 22 0.016 0 0 0.0005 74.91%
0 0.2 0 0 0.016 0.1085 0 0 74.87%
0.0625 0.2 0.0016 22 0 0 0 0 74.85%
0.127 0.1 0 22 0.008 0 0 0 74.81%
0.127 0.1 0 0 0.016 0 0 0 74.80%
0 0 0 22 0.016 0.217 0 0 74.79%
0.127 0 0 0 0.008 0.217 0 0.0005 74.79%
0 0 0.0016 0 0.008 0.217 0 0.001 74.78%
0 0 0 22 0 0.217 0 0.001 74.77%
0.127 0 0 0 0.016 0.217 0 0 74.69%
0.0625 0 0 22 0.016 0 0.0035 0 74.67%
0 0.1 0.0016 0 0.008 0 0 0.001 74.67%
0.0625 0.2 0 22 0 0.217 0 0 74.67%
0 0 0 0 0.016 0.1085 0 0.001 74.65%
0.127 0 0.0016 0 0 0.217 0 0 74.64%
0.127 0 0 22 0.008 0 0 0 74.59%
0.127 0 0.0016 22 0 0 0 0 74.56%
0.127 0.1 0 0 0 0 0 0.0005 74.54%
0.127 0 0.0032 22 0 0 0 0 74.53%
0.0625 0 0 22 0 0 0.007 0.001 74.51%
0 0.2 0.0016 0 0.008 0 0 0 74.48%
0 0 0.0016 22 0.016 0 0 0 74.47%
0 0 0 0 0.00929 0 0.01076 0.00134 74.47%
0 0.2 0 0 0.016 0.1085 0.007 0 74.47%
0 0.1 0.0016 0 0.016 0 0.0035 0 74.45%
0 0 0.0032 22 0 0 0 0.001 74.44%
0 0 0 22 0.016 0 0.007 0 74.42% 0.127 0 0 0 0.016 0.217 0 0 74.42%
0.0625 0 0 22 0.016 0 0 0 74.41%
0.127 0 0 22 0 0.1085 0 0.001 74.36%
0.0625 0 0.0032 0 0 0.217 0.0035 0 74.36%
0 0 0.0032 0 0 0.217 0 0.001 74.32%
0.127 0.1 0 22 0 0 0 0.0005 74.30%
0 0.1 0 0 0.016 0 0 0.0005 74.26%
0 0.2 0.0016 0 0.008 0 0.007 0 74.24%
0.127 0 0 22 0.008 0 0 0.0005 74.23%
0 0.2 0 0 0 0 0.007 0.001 74.22%
0.127 0 0.0032 0 0 0 0 0.0005 74.21%
0 0.1 0 0 0.016 0.1085 0 0.001 74.21%
0 0 0 11 0.016 0 0 0.001 74.20%
0 0.2 0.0016 0 0 0 0 0.0005 74.20%
0 0.2 0.0032 0 0 0 0.007 0 74.19%
0.0625 0.1 0 11 0.016 0 0 0 74.18%
0.127 0 0.0016 0 0.008 0.217 0 0 74.18%
0.127 0 0 0 0.016 0.217 0 0 74.16%
0 0.2 0 0 0.008 0 0.007 0.0005 74.13%
0 0.1 0 0 0.016 0 0.007 0 74.12%
0.127 0.2 0 0 0 0 0.007 0.0005 74.11%
0.0625 0 0 22 0 0 0 0.0005 74.11%
0 0.2 0 0 0.008 0 0 0 74.10%
0 0 0 0 0.016 0 0.0035 0.001 74.10%
0.0625 0.2 0.0016 0 0 0.217 0 0 74.07%
0.127 0.2 0.0016 0 0 0 0.007 0 74.07%
0.127 0 0 22 0 0 0 0.0005 74.04%
0 0 0.0032 0 0 0 0 0.001 74.04%
0 0 0 22 0.008 0.217 0 0.001 74.03%
0.0625 0 0.0016 0 0 0 0 0.001 74.02%
0 0.2 0.0032 0 0 0.217 0 0 74.01%
0.127 0 0.0016 22 0 0 0 0.0005 74.01%
0.0625 0 0 0 0.016 0 0.007 0.0005 73.94%
0.0625 0.2 0 22 0 0 0.007 0 73.94%
0 0 0.0016 0 0.016 0.217 0 0 73.94%
0 0 0 0 0.00929 0.19254 0 0.00067 73.92%
0.127 0.1 0.0016 0 0 0.217 0 0 73.90%
0 0 0.0032 11 0.016 0.217 0 0 73.90%
0 0 0.0032 0 0.016 0 0.007 0 73.89%
0 0.2 0 11 0.016 0.217 0 0 73.88%
0.0625 0.1 0 0 0 0 0 0.001 73.85%
0.0625 0.1 0 22 0 0 0 0 73.83%
0.127 0.2 0.0032 11 0 0 0 0 73.81%
0.127 0 0.0032 22 0.008 0 0 0 73.81% 0 0 0.001305 0 0 0.19254 0.01076 0 73.80%
0 0.1 0 0 0.016 0.217 0.007 0 73.80%
0 0 0.00261 0 0.00929 0.19254 0 0 73.75%
0 0.1 0 22 0.016 0 0.0035 0 73.74%
0 0 0.0016 0 0.016 0 0 0.0005 73.73%
0 0.1 0.0032 0 0.008 0 0 0.0005 73.73%
0.127 0.2 0 0 0 0 0.0035 0.0005 73.73%
0 0 0 0 0.016 0.217 0.007 0.0005 73.70%
0.0625 0 0 11 0.016 0.217 0 0 73.69%
0.0625 0.1 0 0 0 0.217 0 0.001 73.69%
0.127 0.2 0.0016 0 0 0 0.0035 0 73.68%
0.0625 0 0 0 0.016 0 0.0035 0.0005 73.67%
0 0.1 0.0032 11 0.016 0 0 0 73.67%
0 0 0 0 0.008 0.217 0 0.001 73.64%
0.127 0.2 0 0 0 0 0.007 0 73.64%
0.127 0.1 0 0 0 0.217 0 0 73.60%
0 0.2 0 0 0.008 0.217 0 0.001 73.55%
0.0255 0 0.00261 0 0 0.19254 0.01076 0 73.53%
0.127 0 0 22 0.016 0 0 0 73.53%
0 0 0.0032 22 0.016 0 0.0035 0 73.51%
0.127 0.1 0 22 0 0 0 0 73.47%
0 0.2 0 0 0 0 0.007 0.0005 73.47%
0 0 0 22 0.016 0.217 0.0035 0 73.46%
0.0625 0 0 0 0 0 0.0035 0.001 73.46%
0 0 0 22 0.016 0 0.007 0.0005 73.45%
0.0625 0 0.0032 22 0.008 0 0 0 73.44%
0 0.1 0.0032 0 0 0 0.0035 0.001 73.42%
0.0625 0 0 0 0.016 0 0 0.0005 73.41%
0 0 0.0032 0 0.016 0 0 0 73.40%
0.127 0 0.0016 0 0 0 0.007 0.001 73.37%
0.127 0.2 0 0 0 0 0 0.0005 73.34%
0.0625 0.2 0.0016 0 0 0 0.007 0 73.34%
0 0.2 0 22 0.016 0.1085 0 0 73.31%
0 0 0.0032 0 0.016 0.1085 0 0.0005 73.31%
0 0.1 0.0016 0 0 0 0 0.001 73.30%
0 0.1 0.0032 0 0.008 0 0 0 73.30%
0.127 0.2 0.0016 0 0 0 0 0 73.29%
0.127 0.1 0 0 0.016 0 0.0035 0 73.29%
0 0 0 0 0.008 0 0.007 0.001 73.26%
0.127 0.2 0 0 0 0 0.0035 0 73.25%
0.127 0.1 0.0032 0 0 0 0 0 73.24%
0 0 0.0016 0 0.016 0 0.007 0.0005 73.24%
0 0 0.0016 0 0.016 0.217 0.007 0 73.24%
0.127 0 0 0 0.016 0 0 0.0005 73.24% 0.127 0 0 0 0.016 0.1085 0 0.001 73.22%
0 0.2 0.0032 0 0 0 0 0 73.21%
0.127 0.2 0 11 0.008 0 0 0 73.21%
0 0 0.0016 22 0 0 0 0.001 73.20%
0.127 0.1 0 0 0.008 0.217 0 0 73.19%
0.0625 0 0.0032 0 0.016 0.1085 0 0 73.17%
0 0 0 22 0.016 0.1085 0 0.001 73.16%
0 0 0.00261 0 0 0.19254 0.01076 0 73.16%
0 0.1 0 0 0.016 0.217 0 0 73.14%
0.0625 0.1 0 0 0.008 0 0 0 73.10%
0 0 0 0 0.016 0 0.0035 0.0005 73.07%
0 0 0 0 0.016 0.217 0 0.0005 73.04%
0.0625 0 0.0016 0 0.016 0 0 0 73.03%
0 0.2 0.0032 0 0 0 0.0035 0.0005 73.01%
0.127 0.2 0 0 0 0.217 0.007 0 72.99%
0 0.1 0.0032 0 0.016 0.1085 0 0 72.99%
0.127 0 0.0016 0 0 0 0.0035 0.001 72.98%
0 0 0 22 0 0 0.007 0.001 72.93%
0.0625 0 0 22 0.008 0 0 0 72.92%
0 0 0.001305 0 0.00929 0 0 0.00134 72.91%
0 0 0.00261 0 0.00929 0.19254 0.01076 0 72.91%
0 0.2 0 22 0 0 0.007 0 72.90%
0 0 0.0032 11 0.016 0 0 0.0005 72.90%
0 0.2 0 0 0.008 0 0.007 0 72.88%
0 0.2 0 22 0.008 0 0 0 72.88%
0.0625 0.2 0 0 0 0 0.007 0.0005 72.87%
0.127 0.2 0 0 0 0 0 0 72.86%
0.0625 0 0 0 0 0.217 0.0035 0.001 72.83%
0.127 0 0 11 0.016 0.217 0 0 72.82%
0.127 0.1 0 0 0.008 0 0 0 72.80%
0.0625 0 0 22 0 0.217 0 0 72.80%
0.127 0 0 0 0 0.217 0 0.0005 72.77%
0 0 0 11 0.016 0 0.007 0.001 72.73%
0 0 0 0 0.00929 0 0.00538 0.00134 72.72%
0 0 0 0 0.00929 0.19254 0 0.00134 72.70%
0.0625 0 0 0 0.008 0 0.007 0.001 72.67%
0.0625 0.2 0 11 0 0 0 0 72.66%
0 0 0.0032 22 0.008 0.217 0 0 72.66%
0.127 0 0 0 0.016 0.217 0.0035 0 72.65%
0 0.1 0 22 0 0 0 0.001 72.64%
0 0.2 0 22 0 0 0 0.0005 72.62%
0.127 0.1 0 0 0 0.217 0 0.0005 72.61%
0.127 0.2 0 0 0 0.217 0.0035 0 72.61%
0.127 0 0.0032 0 0.016 0 0 0 72.61% 0.127 0 0.0016 0 0 0 0 0.001 72.60%
0.0625 0 0.0032 11 0.016 0 0 0 72.58%
0.0255 0 0 0 0.00929 0.19254 0 0.00134 72.57%
0 0 0.0032 0 0.008 0 0 0.0005 72.57%
0.0625 0 0.0032 0 0.008 0 0 0 72.57%
0 0 0 0 0.00929 0.19254 0.01076 0 72.56%
0 0 0.0016 0 0 0.217 0 0.001 72.52%
0 0.1 0.0032 22 0 0 0 0.001 72.50%
0 0.2 0 0 0.016 0.1085 0.0035 0 72.48%
0 0.2 0.0016 0 0 0 0.007 0 72.48%
0 0.1 0.0016 0 0.016 0 0 0 72.46%
0.127 0.1 0 0 0 0 0.007 0.001 72.45%
0 0.2 0.0032 0 0 0.217 0.007 0 72.45%
0.051 0 0 0 0.00929 0.19254 0 0.00134 72.45%
0 0 0 22 0.016 0 0.0035 0 72.44%
0.0625 0.1 0.0032 22 0 0 0 0 72.43%
0.0625 0.2 0 11 0.008 0 0 0 72.37%
0.0625 0 0 22 0 0 0.0035 0.001 72.35%
0.0625 0.2 0 0 0 0 0.007 0 72.26%
0.127 0.2 0 0 0 0.217 0 0 72.22%
0.0625 0 0.0032 0 0 0.217 0 0 72.20%
0.127 0 0.0032 0 0.016 0 0 0 72.17%
0.127 0.2 0.0032 0 0 0.1085 0 0 72.16%
0 0.1 0 0 0.016 0 0.0035 0 72.13%
0 0.2 0 22 0.008 0 0 0.0005 72.13%
0 0.1 0 11 0.016 0 0 0 72.13%
0.127 0.1 0.0016 22 0 0 0 0 72.13%
0.127 0.1 0 0 0.008 0 0 0.0005 72.09%
0.0625 0 0.0016 0 0 0 0.007 0.001 72.08%
0.127 0.1 0 0 0 0 0.0035 0.001 72.07%
0.127 0 0.0016 0 0 0.217 0 0 72.05%
0 0.2 0.0016 0 0 0 0.0035 0.001 72.05%
0.127 0 0 22 0.016 0 0.0035 0 72.02%
0.0625 0.1 0 22 0.008 0 0 0 72.01%
0.0625 0 0 22 0 0.217 0.007 0 72.01%
0 0.1 0 0 0.008 0 0 0.001 72.00%
0 0 0 0 0.00929 0.19254 0.01076 0.00134 71.90%
0 0 0.0032 0 0.016 0 0.0035 0 71.90%
0.0625 0.2 0 11 0 0 0 0.001 71.89%
0.051 0 0 0 0.00929 0 0 0.00134 71.83%
0 0 0.0032 0 0 0.217 0 0.0005 71.83%
0 0.1 0 0 0.016 0.217 0.0035 0 71.81%
0 0.2 0.0032 0 0 0.217 0 0.0005 71.80%
0.0625 0.2 0 22 0 0 0.0035 0 71.78% 0.127 0.1 0 0 0.016 0 0.007 0 71.78%
0 0.1 0 22 0.016 0 0 0 71.75%
0.127 0 0.0032 0 0.016 0 0 0 71.73%
0.0625 0.2 0.0032 11 0 0 0 0 71.73%
0 0 0 0 0.016 0.217 0.0035 0.0005 71.71%
0.0625 0 0 0 0.008 0.217 0 0.0005 71.71%
0 0 0.0032 22 0 0.217 0 0.0005 71.70%
0.127 0.1 0 0 0 0 0 0.001 71.68%
0 0.2 0 22 0.008 0 0.007 0 71.66%
0.127 0 0 0 0.008 0 0 0.001 71.64%
0.127 0 0 22 0 0 0.007 0 71.63%
0.0625 0 0.0016 0 0.008 0.217 0 0 71.61%
0 0 0.0016 0 0.016 0.217 0 0 71.60%
0.127 0 0.0032 22 0 0 0.007 0 71.56%
0.0625 0 0 0 0.016 0 0.007 0 71.55%
0 0.2 0 0 0.008 0.217 0 0 71.55%
0 0 0.0032 22 0 0 0.0035 0.001 71.54%
0 0 0.0016 22 0 0.217 0 0.001 71.53%
0 0 0.0032 22 0.016 0 0 0 71.53%
0 0 0.0016 22 0.008 0 0 0.001 71.51%
0 0.1 0.0032 0 0.008 0.217 0 0 71.51%
0.127 0.1 0.0016 0 0 0 0 0 71.50%
0 0 0 22 0.016 0.217 0 0 71.48%
0 0 0 22 0.016 0 0.0035 0.0005 71.46%
0.0625 0 0 0 0.008 0 0.0035 0.001 71.46%
0 0 0 0 0.00929 0.19254 0.00538 0 71.44%
0.0625 0 0.0016 0 0 0.217 0 0.0005 71.44%
0.0625 0 0.0032 0 0 0 0 0.0005 71.43%
0 0.2 0 22 0 0 0 0.001 71.37%
0.127 0.1 0 11 0.016 0 0 0 71.34%
0 0.2 0.0016 0 0.008 0 0.0035 0 71.30%
0.0625 0 0 0 0 0 0 0.001 71.30%
0.0625 0 0 0 0.016 0 0.0035 0 71.28%
0 0.1 0.0032 0 0 0 0 0.0005 71.27%
0.127 0 0 0 0.008 0.217 0 0 71.27%
0 0.1 0 0 0 0 0.007 0.001 71.26%
0 0 0.0016 0 0.016 0 0.0035 0.0005 71.26%
0 0 0.0016 0 0.016 0.217 0.0035 0 71.25%
0.127 0 0 22 0 0 0.0035 0 71.25%
0.127 0 0.0032 0 0 0 0.007 0.0005 71.24%
0 0.2 0 0 0 0.217 0 0.001 71.24%
0.0625 0.2 0 0 0 0.217 0 0.0005 71.23%
0 0 0.0032 22 0 0.217 0 0 71.21%
0 0.2 0 0 0.008 0 0.0035 0.0005 71.20% 0.127 0 0.0032 22 0 0 0.0035 0 71.18%
0.0625 0.2 0.0016 0 0 0 0.0035 0 71.18%
0.0625 0.1 0 22 0 0.217 0 0 71.17%
0.127 0 0.0016 0 0 0 0 0.0005 71.15%
0.0625 0 0 22 0.008 0 0 0.0005 71.15%
0 0 0.001305 0 0.00929 0.19254 0 0.00067 71.15%
0 0.2 0.0016 22 0.008 0 0 0 71.15%
0.127 0 0 0 0.016 0.217 0.007 0 71.14%
0 0 0.0032 0 0 0 0.0035 0.001 71.13%
0 0 0.00261 0 0 0.19254 0 0.00134 71.11%
0 0 0 0 0.016 0 0 0.0005 71.09%
0.127 0 0 0 0.008 0 0.0035 0.001 71.08%
0.0625 0 0 11 0.016 0 0 0.0005 71.06%
0.0625 0 0 0 0.016 0 0 0 71.02%
0.0625 0 0 11 0 0 0 0.001 71.00%
0 0.2 0.0032 11 0 0 0 0.001 71.00%
0 0.1 0 22 0.008 0 0 0.001 71.00%
0.0625 0.1 0 0 0.008 0 0 0.0005 70.98%
0 0 0.0032 11 0 0.217 0 0.001 70.94%
0.0625 0.1 0 0 0 0 0.007 0.001 70.93%
0.0625 0.1 0 0 0 0 0 0.0005 70.89%
0.0625 0.2 0 0 0 0.217 0 0 70.86%
0.127 0 0 22 0 0 0 0 70.86%
0.127 0 0.0032 0 0 0 0.0035 0.0005 70.86%
0 0 0 0 0 0.19254 0.01076 0 70.85%
0.127 0 0 0 0.016 0 0 0.0005 70.84%
0.0625 0 0.0032 11 0 0.217 0 0 70.82%
0 0 0 0 0 0.19254 0.01076 0.00067 70.82%
0 0 0.0032 0 0.008 0.1085 0 0.001 70.82%
0 0 0 0 0.016 0.217 0.007 0 70.80%
0.127 0 0.0032 22 0 0 0 0 70.79%
0 0 0 0 0 0.19254 0.01076 0.00134 70.79%
0 0.1 0 0 0.008 0 0.007 0.001 70.78%
0.127 0 0.0016 11 0 0 0 0.001 70.76%
0 0 0 11 0.016 0 0.0035 0.001 70.75%
0.0625 0.1 0.0032 0 0 0 0 0 70.75%
0.051 0 0.001305 0 0 0.19254 0.01076 0 70.74%
0.0625 0 0 0 0 0.217 0 0.0005 70.72%
0.0625 0.2 0 0 0 0 0.0035 0.0005 70.71%
0 0 0.0016 0 0 0 0.007 0.001 70.68%
0 0.2 0 11 0 0 0 0.001 70.67%
0.0625 0 0 0 0 0.217 0 0.001 70.67%
0 0 0.0032 11 0 0 0 0.001 70.66%
0 0 0 22 0.008 0 0 0.001 70.62% 0.0625 0 0.0016 0 0.016 0 0.007 0 70.60%
0.127 0.1 0.0016 0 0 0 0 0.0005 70.59%
0.0255 0 0 0 0.00929 0.19254 0 0 70.58%
0.0625 0 0 22 0.016 0.1085 0 0 70.57%
0 0.2 0 11 0.008 0 0 0.001 70.56%
0 0.2 0.0016 22 0 0 0 0 70.54%
0.127 0 0 22 0.008 0 0 0 70.54%
0 0 0.0032 0 0.008 0.217 0 0 70.53%
0.127 0 0 0 0.008 0 0.007 0.001 70.52%
0.127 0 0 22 0.016 0 0.007 0 70.51%
0 0.2 0 0 0.016 0.1085 0 0 70.50%
0.127 0 0.0032 0 0 0 0 0.0005 70.47%
0.0625 0 0.0032 0 0 0 0.007 0.0005 70.47%
0 0 0.001305 0 0.00929 0.19254 0 0 70.46%
0 0 0 22 0.016 0 0 0 70.45%
0 0 0.0032 11 0.008 0 0 0.001 70.44%
0.0625 0.1 0 0 0.016 0.1085 0 0 70.41%
0 0 0.0032 0 0.016 0 0.007 0 70.40%
0.0255 0 0 0 0 0.19254 0.01076 0 70.40%
0 0 0.0016 0 0.008 0 0 0.001 70.39%
0.0625 0.1 0 0 0.008 0.217 0 0 70.39%
0 0.2 0 22 0 0 0.007 0.001 70.39%
0 0 0.0032 0 0.008 0.217 0.007 0 70.38%
0.0625 0 0 11 0 0.217 0 0.001 70.38%
0.127 0.2 0 11 0 0 0 0 70.35%
0.0625 0 0.0016 0 0.016 0 0.0035 0 70.34%
0 0.2 0 0 0 0 0.0035 0.001 70.34%
0 0 0 0 0.008 0 0.0035 0.001 70.33%
0.127 0 0.0032 22 0 0.1085 0 0 70.31%
0.127 0 0 0 0 0 0.007 0.001 70.31%
0 0.2 0.0032 0 0 0 0.0035 0 70.30%
0.127 0.1 0.0032 0 0 0 0.007 0 70.28%
0 0 0 0 0.016 0.1085 0 0.001 70.27%
0 0 0.0032 0 0 0.217 0.007 0.0005 70.27%
0 0 0.0016 0 0.016 0 0.007 0 70.26%
0.127 0 0 0 0 0.1085 0 0.001 70.25%
0.0625 0 0 0 0.008 0 0 0.001 70.25%
0.127 0 0.0016 0 0 0.217 0.007 0 70.23%
0.127 0 0.0032 0 0.016 0 0.0035 0 70.22%
0.0625 0 0 22 0 0 0 0.001 70.19%
0 0 0.001305 0 0.00929 0.19254 0.01076 0 70.17%
0.127 0 0.0016 22 0.008 0 0 0 70.16%
0 0 0.0016 0 0.008 0 0.007 0.001 70.15%
0 0.1 0 0 0.016 0 0 0 70.15% 0.127 0.1 0.0016 0 0.008 0 0 0 70.15%
0 0.2 0.0032 22 0 0 0.007 0 70.14%
0.0625 0.2 0 0 0 0 0.0035 0 70.10%
0.0625 0.2 0.0032 0 0 0.1085 0 0 70.08%
0.0625 0 0.0016 0 0.016 0 0 0 70.07%
0.0625 0 0.0032 22 0 0 0 0 70.07%
0.0625 0.2 0 0 0 0.217 0.007 0 70.07%
0 0.2 0.0016 0 0.008 0.217 0 0 70.06%
0 0.2 0 11 0.008 0 0 0 70.06%
0.127 0.1 0 0 0 0.217 0 0 70.03%
0 0 0.0016 22 0.016 0 0 0 70.01%
0.0625 0 0 0 0.008 0 0 0.0005 70.01%
0.127 0 0 0 0.008 0 0 0.0005 69.99%
0 0.2 0.0016 22 0 0 0 0.001 69.99%
0.127 0 0 0 0 0.217 0.007 0.0005 69.98%
0.051 0 0 0 0 0.19254 0.01076 0 69.95%
0 0.2 0 0 0.008 0 0.0035 0 69.95%
0.127 0 0 0 0 0 0.0035 0.001 69.93%
0.0625 0 0.0016 0 0 0 0.0035 0.001 69.92%
0 0 0.0032 0 0.016 0 0 0 69.92%
0.127 0 0 11 0 0.217 0 0.0005 69.92%
0.127 0.1 0.0032 0 0 0 0.0035 0 69.89%
0.127 0.2 0 0 0 0.1085 0 0.001 69.88%
0 0 0 0 0.016 0.1085 0.007 0.001 69.87%
0 0.2 0.0032 22 0 0 0 0.0005 69.87%
0.127 0 0.0016 22 0 0 0 0 69.85%
0.0625 0 0 22 0 0.217 0.0035 0 69.84%
0.127 0 0.0016 0 0 0.217 0.0035 0 69.84%
0.127 0 0.0032 0 0.008 0 0 0 69.84%
0 0.1 0 0 0.016 0.217 0 0 69.83%
0.127 0 0.0016 0 0.016 0 0 0 69.83%
0.127 0.2 0 11 0 0 0 0.0005 69.82%
0.127 0 0 11 0.008 0 0 0.001 69.82%
0 0.1 0 11 0.016 0 0 0.0005 69.80%
0.0625 0.1 0.0032 0 0 0 0.007 0 69.78%
0.127 0 0.0016 0 0 0.1085 0 0.001 69.74%
0 0 0 0 0.016 0.217 0 0.0005 69.73%
0.127 0.2 0 11 0 0.217 0 0 69.70%
0.127 0 0 22 0.016 0.1085 0 0 69.70%
0 0.2 0.0032 11 0.008 0 0 0 69.68%
0.0625 0 0 11 0.016 0 0 0 69.67%
0 0 0 0 0.00929 0.19254 0.01076 0.00067 69.66%
0 0 0.0032 22 0 0.217 0.007 0 69.66%
0.127 0 0.0016 11 0 0.217 0 0 69.62% 0 0 0 0 0.00929 0 0 0.00134 69.62%
0 0 0 0 0.016 0 0.007 0.0005 69.62%
0.0625 0.2 0 22 0 0 0 0 69.62%
0 0 0.00261 0 0.00929 0 0 0.00067 69.60%
0.0625 0 0 0 0.008 0.217 0 0 69.60%
0 0 0.00261 0 0.00929 0.19254 0 0 69.60%
0.127 0 0 0 0 0.217 0.0035 0.0005 69.59%
0 0.2 0 0 0 0 0.0035 0.0005 69.59%
0 0 0 0 0.008 0.217 0.007 0.001 69.58%
0 0 0.00261 0 0 0.19254 0.01076 0 69.56%
0.127 0 0 11 0 0.217 0 0 69.55%
0.0625 0.1 0.0016 0 0.008 0 0 0 69.54%
0.127 0 0 0 0 0 0 0.001 69.54%
0 0.1 0.0032 0 0 0 0 0.001 69.54%
0 0 0.00261 0 0 0.19254 0.01076 0.00067 69.53%
0.0625 0 0.0016 0 0 0.217 0 0 69.53%
0 0 0.0016 22 0.016 0 0.007 0 69.52%
0.127 0.1 0.0032 0 0 0 0 0 69.51%
0 0 0.00261 0 0 0.19254 0.01076 0.00134 69.50%
0 0 0 22 0.016 0 0 0.0005 69.48%
0.0255 0 0.00261 0 0.00929 0.19254 0 0 69.47%
0.127 0 0.0016 0 0 0.217 0 0 69.46%
0.0625 0 0.0016 22 0 0 0 0 69.46%
0 0 0 22 0.008 0 0.007 0.001 69.40%
0.127 0 0 0 0.008 0.217 0 0 69.35%
0 0.2 0.0032 0 0 0.217 0 0 69.35%
0.051 0 0.00261 0 0.00929 0.19254 0 0 69.35%
0.127 0 0 0 0.016 0 0.0035 0.0005 69.33%
0 0 0 22 0 0.217 0.007 0.001 69.31%
0.127 0.1 0 11 0 0 0 0.001 69.27%
0 0 0.0016 0 0.016 0 0 0.0005 69.27%
0 0 0.0016 0 0.016 0.217 0 0 69.27%
0.127 0 0 11 0 0 0 0.001 69.25%
0.127 0.2 0.0016 11 0 0 0 0 69.23%
0 0 0.00261 0 0.00929 0.09627 0 0.00134 69.22%
0.127 0 0 0 0 0.217 0 0.0005 69.21%
0.127 0.2 0 0 0 0.1085 0 0 69.17%
0 0.2 0.0032 22 0 0 0 0 69.17%
0 0 0 0 0 0.217 0.007 0.001 69.17%
0 0.2 0.0032 0 0 0 0 0.0005 69.13%
0.127 0 0 22 0 0 0.007 0.0005 69.12%
0.0625 0 0.0032 22 0 0 0.007 0 69.11%
0 0 0.0032 0 0 0.1085 0 0.001 69.05%
0 0 0 22 0 0 0.0035 0.001 69.05% 0 0 0.0032 22 0 0 0 0.0005 69.04%
0 0.2 0 22 0 0 0.0035 0 69.02%
0.0625 0.2 0.0016 0 0 0 0 0 69.02%
0 0 0.0016 0 0 0.217 0.007 0.001 69.01%
0 0 0.00261 0 0 0 0.01076 0.00134 68.99%
0 0 0 22 0.016 0 0.007 0 68.99%
0 0.2 0.0032 0 0 0.1085 0 0.001 68.98%
0 0 0.0032 11 0.016 0 0 0 68.97%
0.0625 0 0.0032 0 0.008 0 0 0 68.93%
0 0.1 0.0032 0 0.008 0 0.007 0 68.90%
0.127 0.1 0 0 0 0 0 0.0005 68.85%
0.127 0.2 0 22 0 0.1085 0 0 68.83%
0 0 0 0 0.016 0.217 0.0035 0 68.81%
0.127 0 0.0032 0 0 0.1085 0 0.0005 68.80%
0.0625 0.1 0 0 0 0 0.0035 0.001 68.77%
0 0 0 11 0.016 0 0 0.001 68.76%
0.127 0.1 0 0 0.008 0 0 0 68.76%
0 0 0 11 0.016 0 0 0.0005 68.74%
0.127 0 0 22 0 0 0.0035 0.0005 68.73%
0 0.2 0 22 0.008 0 0.0035 0 68.73%
0.127 0 0.0032 0 0.016 0 0.007 0 68.71%
0 0 0.00261 0 0.00929 0 0 0.00134 68.71%
0 0.1 0 0 0.016 0 0.007 0 68.68%
0 0 0 0 0.008 0.217 0 0.001 68.68%
0.127 0 0.0016 0 0.008 0 0 0.0005 68.65%
0 0.1 0 0 0.008 0.217 0 0.001 68.63%
0.127 0 0 0 0 0.217 0.007 0 68.62%
0 0.2 0.0016 0 0 0 0.0035 0 68.60%
0.0255 0 0.00261 0 0.00929 0 0 0.00134 68.58%
0 0.2 0.0032 0 0 0.217 0.0035 0 68.57%
0.127 0.1 0 22 0 0 0.007 0 68.55%
0.0625 0.2 0 0 0 0 0 0.0005 68.55%
0.127 0 0 11 0.016 0 0 0.0005 68.50%
0.0625 0 0.0032 0 0 0 0.007 0 68.48%
0 0 0 0 0.00929 0.09627 0 0.00134 68.47%
0 0.2 0.0016 0 0 0.217 0 0.001 68.46%
0.051 0 0.00261 0 0.00929 0 0 0.00134 68.45%
0 0 0.0032 22 0.008 0 0 0.0005 68.45%
0.0625 0 0 11 0.008 0 0 0.001 68.43%
0 0 0.0032 0 0.016 0 0.0035 0 68.42%
0.127 0 0.0016 0 0.016 0 0 0 68.41%
0 0.1 0 0 0.008 0 0 0.0005 68.40%
0.0625 0 0 0 0.016 0.1085 0 0.0005 68.38%
0.0625 0 0 0 0 0 0.007 0.001 68.38% 0 0.2 0.0016 0 0.008 0 0 0 68.37%
0.0625 0.1 0.0016 0 0 0 0 0 68.36%
0.127 0 0 22 0 0 0 0.0005 68.35%
0.127 0.2 0 0 0.008 0.1085 0 0 68.32%
0.0625 0 0.0032 0 0 0 0.0035 0.0005 68.31%
0 0 0.001305 0 0 0.19254 0.01076 0 68.30%
0 0 0.0016 0 0.016 0 0.0035 0 68.28%
0 0.2 0 0 0.008 0 0 0.0005 68.27%
0.0625 0.1 0 0 0 0.217 0 0 68.26%
0.127 0 0 22 0 0.1085 0 0 68.26%
0.127 0 0 0 0 0.217 0.0035 0 68.23%
0 0 0.0032 0 0 0 0.007 0.001 68.23%
0 0 0.001305 0 0.00929 0 0 0.00067 68.21%
0 0 0.0032 0 0.008 0 0.007 0.0005 68.17%
0 0.1 0.0032 0 0.008 0 0 0 68.17%
0.127 0.1 0 22 0 0 0.0035 0 68.17%
0 0.2 0.0016 0 0 0 0 0.001 68.16%
0 0 0 22 0 0.217 0 0.001 68.16%
0.127 0 0.0032 11 0 0 0 0.0005 68.09%
0.127 0.2 0 0 0 0 0.007 0 67.94%
0.0625 0.2 0 0 0 0 0 0 67.94%
0.0625 0.2 0 0 0 0.217 0.0035 0 67.91%
0.127 0 0.0032 0 0.016 0.1085 0 0 67.90%
0 0 0 0 0.016 0.1085 0.0035 0.001 67.88%
0 0.2 0.0032 0 0.008 0.1085 0 0 67.88%
0.0625 0 0 22 0 0 0.007 0 67.88%
0 0.1 0 0 0.008 0 0.0035 0.001 67.85%
0.127 0 0 0 0 0.217 0 0 67.84%
0.127 0 0.0032 0 0 0 0.007 0 67.84%
0.127 0 0 0 0.016 0 0.007 0.0005 67.82%
0 0.1 0 22 0.008 0 0 0 67.80%
0.127 0.1 0 22 0 0 0 0 67.78%
0 0 0.0032 0 0 0.217 0.007 0 67.77%
0.0625 0 0.0016 0 0.008 0 0 0.0005 67.77%
0.0625 0 0.0016 0 0 0 0 0.001 67.76%
0.127 0 0.0032 0 0.008 0 0 0 67.75%
0.0625 0 0.0016 0 0 0 0 0.0005 67.73%
0.0625 0 0.0032 0 0.008 0 0.007 0 67.72%
0 0 0.0032 22 0.016 0.1085 0 0 67.69%
0.0625 0 0 22 0 0.217 0 0 67.68%
0 0 0 0 0.00929 0.09627 0 0.00067 67.68%
0 0 0.0032 22 0.008 0 0 0 67.67%
0.0625 0.1 0.0016 0 0 0.217 0 0 67.66%
0 0 0.0032 22 0 0 0 0.001 67.66% 0 0 0 0 0.016 0 0.0035 0.0005 67.63%
0.0625 0.1 0.0032 0 0 0 0.0035 0 67.62%
0.127 0 0 11 0.008 0.217 0 0 67.62%
0 0 0.0032 0 0 0 0.007 0.0005 67.61%
0.0625 0 0 0 0.016 0 0.007 0 67.61%
0 0.2 0.0032 11 0 0 0 0 67.60%
0.0625 0 0.0016 22 0.008 0 0 0 67.59%
0 0.2 0 0 0.008 0.217 0 0.0005 67.58%
0.127 0.1 0 0 0.016 0.1085 0 0 67.57%
0.127 0.2 0 0 0 0 0.0035 0 67.56%
0.0625 0.1 0 22 0 0 0 0.0005 67.55%
0 0 0.0016 22 0.016 0 0.0035 0 67.54%
0 0 0.0032 0 0.008 0.217 0 0 67.52%
0.0625 0.1 0 0 0.008 0 0 0 67.51%
0 0 0 0 0.016 0.217 0.007 0 67.49%
0 0.2 0 0 0.008 0.217 0.007 0 67.49%
0 0.2 0 22 0.008 0.217 0 0 67.49%
0.0625 0 0.0016 22 0 0 0 0.0005 67.49%
0.0625 0.2 0 0 0.008 0.1085 0 0 67.48%
0 0.1 0.0016 11 0.016 0 0 0 67.46%
0.127 0 0.0032 0 0 0 0.0035 0 67.46%
0 0 0.0032 0 0.008 0.217 0.0035 0 67.45%
0 0 0.0032 0 0.016 0.1085 0 0 67.44%
0 0 0.0032 0 0.008 0 0 0.0005 67.44%
0.127 0 0 0 0.008 0.217 0 0 67.43%
0 0.2 0.0032 22 0 0.217 0 0 67.43%
0 0 0 0 0.00929 0.19254 0.01076 0 67.42%
0 0.2 0.0032 0 0 0 0.007 0 67.40%
0 0 0 0 0.008 0 0 0.001 67.39%
0 0 0 11 0.016 0.217 0 0.0005 67.38%
0 0.1 0 0 0 0 0.0035 0.001 67.38%
0.0625 0 0 0 0.016 0 0.0035 0 67.34%
0.0625 0 0 22 0.008 0 0 0 67.33%
0.0625 0 0 22 0 0.1085 0 0.001 67.33%
0 0 0 0 0.00929 0.19254 0.00538 0.00134 67.32%
0.127 0 0.0032 11 0.016 0 0 0 67.30%
0.0255 0 0 0 0.00929 0.19254 0.01076 0 67.30%
0.0255 0 0 0 0.00929 0 0 0.00134 67.28%
0 0 0.0032 0 0 0 0 0.001 67.25%
0.127 0.1 0 0 0 0.217 0.007 0 67.24%
0 0 0.0016 0 0.008 0 0.0035 0.001 67.22%
0 0.1 0.0032 0 0 0 0.007 0 67.19%
0.0625 0 0.0016 11 0.016 0 0 0 67.19%
0.051 0 0 0 0.00929 0.19254 0.01076 0 67.17% 0 0 0 0 0.00929 0.19254 0 0 67.17%
0 0 0.0032 0 0 0.217 0 0.0005 67.17%
0 0.1 0.0032 0 0 0.217 0 0.0005 67.15%
0.127 0 0 0 0.008 0.1085 0 0.001 67.10%
0 0 0 0 0.004645 0.19254 0 0.00134 67.09%
0.0625 0 0 0 0.016 0 0 0 67.08%
0.127 0 0.0032 0 0 0 0 0 67.07%
0.127 0 0 0 0.016 0 0 0 67.04%
0 0.2 0 0 0.008 0 0 0 67.01%
0 0.1 0.0032 0 0 0.217 0 0 67.01%
0 0 0 22 0.016 0 0.0035 0 67.00%
0.127 0 0.0016 0 0.016 0 0 0 67.00%
0.051 0 0 0 0 0.19254 0.01076 0 66.96%
0 0.1 0.0032 22 0.008 0 0 0 66.95%
0.0625 0 0.0032 22 0 0 0.0035 0 66.95%
0 0 0 0 0.004645 0.19254 0.01076 0 66.90%
0 0 0.0016 0 0 0.217 0 0.001 66.88%
0.127 0 0 0 0.008 0.217 0.0035 0 66.87%
0.0625 0 0 22 0 0 0 0.0005 66.87%
0.127 0.1 0 0 0 0.217 0.0035 0 66.85%
0 0 0 0 0.016 0.217 0 0 66.83%
0 0 0 0 0.00929 0 0 0.00067 66.83%
0 0 0.0016 0 0 0 0.0035 0.001 66.80%
0.127 0.1 0 0 0 0 0.007 0 66.79%
0.127 0.1 0.0016 0 0 0 0 0 66.79%
0.0625 0.2 0 0 0 0.1085 0 0.001 66.77%
0.0255 0 0.001305 0 0 0.19254 0.01076 0 66.77%
0 0.1 0 0 0.016 0 0.0035 0 66.69%
0 0.1 0 11 0.016 0 0 0 66.69%
0.127 0 0 22 0 0.1085 0 0.0005 66.68%
0 0 0 22 0.008 0 0 0.0005 66.67%
0 0 0 0 0.008 0.217 0.0035 0.001 66.65%
0 0 0.00261 0 0 0.19254 0 0.00067 66.63%
0 0 0 22 0.008 0.217 0 0 66.62%
0.0625 0.1 0 0 0 0 0 0.001 66.61%
0.0625 0.1 0 22 0 0 0 0 66.58%
0 0.2 0 0 0.008 0.217 0 0 66.58%
0 0 0.0032 0 0.016 0.1085 0.007 0 66.57%
0 0 0.0032 22 0 0.217 0 0 66.55%
0.0625 0 0.0032 0 0.008 0 0.0035 0 66.51%
0 0.2 0 22 0 0 0.0035 0.001 66.51%
0.127 0 0 22 0.008 0 0 0 66.50%
0.127 0.1 0 0 0 0.217 0 0 66.47%
0 0 0 22 0.008 0 0.0035 0.001 66.46% 0 0.2 0 0 0 0 0 0.001 66.46%
0 0.2 0.0016 0 0 0 0.007 0.0005 66.44%
0 0.2 0.0016 0 0 0 0 0.0005 66.44%
0.127 0 0.0016 0 0 0 0 0.0005 66.44%
0 0.2 0.0032 0 0 0 0 0 66.42%
0.127 0.1 0 0 0 0 0.0035 0 66.41%
0 0.1 0.0032 22 0 0 0 0 66.40%
0 0 0.0032 0 0 0.217 0.0035 0.0005 66.39%
0 0 0.0016 11 0.016 0.217 0 0 66.38%
0 0.1 0 11 0.016 0.217 0 0 66.37%
0 0.1 0 0 0 0.217 0 0.001 66.32%
0.0625 0 0.0032 0 0 0 0.0035 0 66.32%
0.0625 0 0 0 0 0.1085 0 0.001 66.32%
0.127 0 0 0 0.008 0.217 0.007 0 66.31%
0 0 0.0016 0 0.016 0 0 0 66.29%
0 0 0.00261 0 0.00929 0.19254 0.00538 0 66.27%
0 0.2 0.0032 22 0 0 0.0035 0 66.26%
0.0625 0 0.0016 0 0.016 0.1085 0 0 66.24%
0 0.1 0 0 0.016 0.1085 0 0 66.24%
0.0625 0 0 0 0 0 0.0035 0.001 66.22%
0.051 0 0.00261 0 0 0.19254 0 0.00134 66.20%
0 0 0.00261 0 0.004645 0 0 0.00134 66.18%
0 0 0 0 0.008 0 0.007 0.001 66.17%
0.0625 0 0.0032 0 0 0 0 0.0005 66.15%
0.0625 0 0 0 0.008 0.217 0 0 66.14%
0.127 0.1 0 11 0 0.217 0 0 66.06%
0.0625 0.1 0.0016 0 0 0 0 0.0005 66.04%
0.127 0.2 0.0016 0 0 0.1085 0 0 66.04%
0 0 0.001305 0 0 0 0.01076 0.00134 66.03%
0.051 0 0 0 0.00929 0.19254 0 0 66.03%
0.127 0.1 0 0 0 0 0 0 66.02%
0.127 0.1 0.0032 11 0 0 0 0 66.01%
0 0 0 0 0.00929 0 0.01076 0.00134 65.99%
0.127 0 0 11 0 0.217 0 0 65.99%
0 0 0.0032 11 0.016 0 0.007 0 65.97%
0 0.1 0.0032 0 0.008 0 0.0035 0 65.97%
0.127 0 0 0 0.008 0 0 0.0005 65.95%
0 0 0 0 0.00929 0.19254 0 0.00067 65.95%
0.127 0 0 22 0.008 0 0.0035 0 65.94%
0.127 0 0 22 0 0 0.007 0 65.94%
0 0.2 0 22 0 0.217 0 0 65.94%
0.0625 0 0.0016 11 0 0 0 0.001 65.92%
0.127 0 0.0016 22 0 0 0.007 0 65.91%
0 0 0 0 0.016 0.1085 0 0.001 65.90% 0.0625 0.1 0.0016 22 0 0 0 0 65.89%
0.0625 0.1 0 0 0 0.217 0 0.0005 65.86%
0 0.1 0 0 0.016 0.1085 0 0.0005 65.85%
0.0255 0 0 0 0.00929 0.19254 0 0.00067 65.82%
0.127 0 0 0 0.016 0.1085 0 0.0005 65.82%
0 0 0.0016 0 0.016 0 0.007 0 65.80%
0.0625 0.2 0 0 0 0.1085 0 0 65.79%
0 0.2 0 0 0.008 0 0.007 0 65.79%
0 0.2 0 22 0.008 0 0 0 65.79%
0 0 0.0032 22 0 0.217 0.0035 0 65.77%
0 0.2 0 0 0 0.217 0.007 0.001 65.77%
0.0625 0.2 0 0 0 0.217 0 0 65.75%
0.0625 0 0 11 0.016 0 0 0 65.73%
0.0625 0 0 22 0 0 0.0035 0 65.71%
0.0625 0 0 0 0.008 0.1085 0 0.001 65.71%
0 0.2 0 0 0 0 0 0.0005 65.71%
0.127 0 0 11 0.016 0 0 0 65.70%
0.051 0 0 0 0.00929 0.19254 0 0.00067 65.70%
0 0 0.001305 0 0 0.19254 0 0.00134 65.70%
0.127 0 0.0032 11 0 0 0 0 65.69%
0.127 0 0.0032 0 0.008 0 0 0 65.66%
0 0 0 0 0.016 0 0 0.0005 65.65%
0.127 0.1 0.0032 0 0 0.1085 0 0 65.64%
0.127 0 0 0 0 0.1085 0 0.001 65.62%
0.127 0.1 0 11 0 0 0 0 65.62%
0.0625 0 0 0 0 0.217 0 0.0005 65.60%
0.0625 0 0.0016 0 0.008 0 0 0 65.58%
0.0625 0 0.0016 0 0 0.217 0.007 0 65.58%
0 0 0 11 0.008 0 0 0.001 65.57%
0.127 0 0 22 0 0 0.0035 0 65.55%
0 0 0.0016 22 0.016 0 0 0 65.55%
0 0.1 0.0016 0 0 0 0.007 0.001 65.54%
0 0.1 0.0016 0 0 0 0 0.001 65.54%
0.127 0 0 0 0.016 0 0.0035 0 65.53%
0.127 0 0.0016 22 0 0 0.0035 0 65.52%
0 0.2 0.0016 0 0 0.217 0 0 65.51%
0 0.1 0.0016 0 0.008 0 0 0 65.50%
0 0 0 0 0.016 0.217 0.0035 0 65.50%
0.127 0 0.0016 0 0.016 0 0.0035 0 65.49%
0 0 0 11 0.016 0.217 0 0 65.49%
0 0 0.0032 11 0.016 0 0 0 65.49%
0 0.2 0 0 0 0 0.007 0.001 65.48%
0 0.1 0.0032 0 0 0 0.007 0.0005 65.46%
0.0625 0.1 0.0032 0 0 0 0 0 65.46% 0 0.1 0.0032 0 0 0.217 0.007 0 65.45%
0 0 0.0016 22 0 0 0.007 0.001 65.44%
0 0 0.0016 22 0 0 0 0.001 65.44%
0.127 0.1 0 0 0 0.1085 0 0.001 65.43%
0 0 0 22 0 0.217 0.0035 0.001 65.42%
0.127 0.2 0 11 0 0 0.007 0 65.42%
0.0625 0.2 0 11 0 0 0 0 65.42%
0 0 0.0032 0 0.008 0 0.007 0 65.39%
0.0625 0 0.0016 0 0 0.217 0 0 65.39%
0 0 0.0016 11 0.016 0 0 0.0005 65.38%
0.127 0 0 22 0.008 0 0.007 0 65.38%
0 0 0.0032 0 0 0.1085 0.007 0.001 65.37%
0 0 0 22 0.008 0.217 0 0.0005 65.36%
0.0625 0 0.0032 0 0.008 0 0 0 65.30%
0 0.2 0 0 0.008 0.1085 0 0.001 65.30%
0 0 0 0 0 0.217 0.0035 0.001 65.28%
0 0 0.0032 0 0.008 0 0.0035 0.0005 65.24%
0 0.1 0.0016 0 0.016 0.1085 0 0 65.24%
0 0.1 0 11 0.016 0 0.007 0 65.22%
0.0255 0 0 0 0 0.19254 0.01076 0 65.20%
0 0 0 22 0 0 0 0.001 65.17%
0.127 0 0 22 0 0 0 0 65.17%
0 0.2 0 22 0 0 0 0 65.14%
0.127 0 0.0016 22 0 0 0 0 65.13%
0.127 0 0 0 0 0 0.007 0.0005 65.13%
0 0 0.0016 0 0 0.217 0.0035 0.001 65.13%
0.127 0 0.0032 0 0.008 0 0.0035 0 65.10%
0.0625 0 0 0 0.008 0.217 0.007 0 65.10%
0.127 0 0 11 0 0 0 0.0005 65.07%
0.0625 0 0 0 0.016 0.1085 0 0 65.06%
0.127 0 0.0016 0 0.008 0 0 0 65.05%
0.127 0 0 0 0 0.217 0.007 0 65.05%
0.127 0.2 0 11 0 0 0.0035 0 65.04%
0.0625 0.2 0 11 0 0 0 0.0005 65.03%
0.0625 0.2 0 0 0 0 0.007 0 65.02%
0 0 0.0032 0 0.016 0.1085 0 0 65.02%
0 0 0 22 0.016 0 0 0 65.02%
0.0625 0.1 0 0 0 0 0.007 0 65.00%
0 0 0 22 0 0.217 0 0.0005 64.96%
0.0625 0.2 0.0016 11 0 0 0 0 64.95%
0.051 0 0 0 0.00929 0 0 0.00134 64.94%
0 0.2 0 11 0.016 0.1085 0 0 64.93%
0 0.1 0 0 0.008 0 0 0.001 64.91%
0.0625 0 0.0016 0 0 0.1085 0 0.001 64.91% 0.127 0.2 0 0 0 0.1085 0 0.0005 64.89%
0 0 0 0 0.00929 0.19254 0.00538 0 64.88%
0 0 0 0 0.00929 0 0.01076 0.00067 64.88%
0.0625 0 0 0 0 0.217 0.007 0 64.86%
0 0.1 0.0016 0 0 0.217 0 0.001 64.85%
0 0 0.0032 11 0 0 0.007 0.001 64.85%
0.0255 0 0 0 0.00929 0.19254 0 0 64.83%
0.0625 0 0 0 0 0.217 0.007 0.0005 64.81%
0 0 0.0032 22 0 0.1085 0 0.001 64.80%
0.0625 0 0.0032 22 0 0 0 0 64.79%
0 0.2 0 0 0 0.217 0.007 0 64.78%
0.127 0 0 0 0 0 0.0035 0.0005 64.75%
0 0.2 0 0 0 0 0.007 0.0005 64.73%
0.127 0.1 0 0 0.008 0 0 0 64.72%
0 0.2 0.0016 0 0 0 0.007 0 64.71%
0 0.2 0.0016 0 0 0 0 0 64.71%
0 0.2 0.0032 0 0 0.217 0 0 64.69%
0 0 0.0016 22 0.008 0.217 0 0 64.68%
0 0 0.00261 0 0 0.19254 0 0.00134 64.68%
0.127 0 0 0 0 0.217 0.0035 0 64.66%
0 0.1 0.0032 22 0 0.217 0 0 64.66%
0.127 0 0.0016 22 0 0.1085 0 0 64.65%
0.127 0.2 0 11 0 0 0 0 64.65%
0.127 0 0 0 0.016 0 0 0 64.65%
0 0.2 0 0 0 0.217 0 0.001 64.62%
0.127 0 0 0 0 0 0.007 0.001 64.62%
0 0 0.0032 22 0 0 0.007 0 64.61%
0 0 0.0032 0 0.016 0.1085 0.0035 0 64.58%
0 0.2 0 0 0.008 0.217 0.0035 0 64.55%
0.127 0.2 0 0 0 0.1085 0 0 64.54%
0.127 0 0.0032 0 0.008 0 0.007 0 64.54%
0 0.1 0 22 0.016 0.1085 0 0 64.53%
0 0 0.0032 0 0.008 0.217 0 0 64.51%
0 0 0 22 0.016 0.1085 0 0 64.49%
0 0.1 0.0032 0 0 0 0 0.0005 64.49%
0.0625 0 0.0032 0 0 0.1085 0 0.0005 64.48%
0 0 0.00261 0 0 0.19254 0.00538 0 64.47%
0.127 0 0.0032 0 0 0.1085 0 0 64.47%
0 0 0 22 0.016 0.1085 0 0.0005 64.45%
0.0625 0 0 0 0.008 0 0 0.0005 64.42%
0 0 0.001305 0 0.00929 0.19254 0 0 64.40%
0.127 0 0 0 0 0 0 0.0005 64.36%
0 0 0.0032 0 0 0 0.0035 0.001 64.35%
0.127 0 0 22 0.008 0.1085 0 0 64.35% 0.0625 0.1 0 0 0.008 0 0.007 0 64.34%
0.127 0 0 11 0 0 0.007 0.001 64.33%
0.0625 0 0.0032 22 0 0.1085 0 0 64.31%
0 0 0.0016 0 0.008 0 0 0.001 64.28%
0.127 0 0 0 0 0.217 0 0 64.28%
0.0255 0 0.001305 0 0.00929 0.19254 0 0 64.27%
0 0 0.0016 0 0.016 0.1085 0 0.0005 64.25%
0.127 0 0 0 0 0 0.0035 0.001 64.23%
0.0625 0.1 0 11 0 0 0 0.001 64.20%
0 0 0 22 0 0 0.007 0.001 64.19%
0 0 0 0 0.016 0 0.007 0.0005 64.18%
0 0 0 0 0.016 0.217 0.007 0 64.18%
0.0625 0 0 22 0.008 0 0.007 0 64.17%
0 0.2 0 22 0 0 0.007 0 64.16%
0.0625 0 0.0032 0 0 0 0 0 64.16%
0.127 0.1 0 0 0.008 0 0.0035 0 64.15%
0.051 0 0.001305 0 0.00929 0.19254 0 0 64.15%
0 0.2 0 0 0 0.217 0 0.0005 64.13%
0 0 0.0016 0 0.008 0.217 0 0.0005 64.11%
0.127 0 0.0016 11 0.016 0 0 0 64.11%
0.127 0 0.0032 0 0 0 0.007 0 64.10%
0.0625 0 0 0 0 0 0 0.001 64.06%
0 0.1 0.0032 11 0 0 0 0.001 64.04%
0 0 0.001305 0 0.00929 0.09627 0 0.00134 64.03%
0.127 0 0 0 0.016 0 0.007 0 64.02%
0 0 0.0032 11 0.016 0 0.0035 0 63.99%
0 0.2 0 0 0 0 0.007 0 63.98%
0.051 0 0 0 0 0.19254 0.01076 0 63.98%
0.127 0 0.0016 0 0.016 0 0.007 0 63.98%
0 0.1 0.0016 0 0.008 0 0 0.0005 63.97%
0.0625 0 0 22 0 0 0.007 0.0005 63.95%
0.051 0 0 0 0 0.19254 0.01076 0.00067 63.95%
0.127 0 0 11 0 0 0.0035 0.001 63.94%
0 0 0 0 0.016 0.1085 0 0.0005 63.94%
0.127 0.1 0 0 0 0 0.007 0.0005 63.93%
0.051 0 0 0 0 0.19254 0.01076 0.00134 63.91%
0.127 0.1 0 22 0 0.1085 0 0 63.91%
0 0.1 0 22 0 0 0 0.001 63.90%
0 0 0.0032 0 0 0.217 0.0035 0 63.89%
0.0625 0 0 0 0.008 0.217 0.0035 0 63.89%
0 0.2 0 22 0 0 0 0.0005 63.88%
0 0 0.0032 11 0 0 0 0.001 63.87%
0 0 0.00261 0 0.004645 0.19254 0.01076 0 63.86%
0 0.1 0.0016 22 0 0 0 0.001 63.83% 0 0.2 0.0032 0 0 0.1085 0 0 63.82%
0 0 0.0016 0 0.016 0 0.0035 0 63.82%
0.0625 0 0.0032 11 0 0 0 0.0005 63.77%
0.0625 0 0 11 0 0 0 0.001 63.76%
0 0 0.0032 0 0 0 0.0035 0.0005 63.73%
0.127 0 0.0032 0 0 0 0.0035 0 63.72%
0 0 0 0 0.008 0.217 0 0.001 63.71%
0.0625 0 0 0 0.016 0 0.007 0 63.67%
0.0625 0.1 0 22 0 0 0.007 0 63.67%
0.0625 0.1 0 0 0 0 0 0.0005 63.65%
0.127 0 0 22 0 0.1085 0 0 63.63%
0.127 0.1 0 0 0.008 0 0.007 0 63.59%
0 0.1 0 0 0.008 0 0.007 0 63.57%
0.127 0 0 11 0 0 0 0.001 63.55%
0.0625 0 0 22 0 0 0 0 63.55%
0 0 0 22 0.016 0 0.007 0 63.55%
0.127 0.1 0 0 0 0 0.0035 0.0005 63.54%
0 0 0 22 0.008 0 0 0.001 63.53%
0 0.2 0.0032 0 0 0 0.0035 0 63.52%
0 0 0 0 0.016 0.217 0 0 63.52%
0 0 0.001305 0 0.00929 0 0 0.00134 63.51%
0.127 0 0.0032 0 0.008 0.1085 0 0 63.51%
0 0.1 0 0 0 0 0 0.001 63.50%
0 0 0.0016 0 0.008 0 0 0.0005 63.46%
0 0 0 0 0 0.19254 0.01076 0 63.44%
0 0.2 0 0 0 0.1085 0 0.001 63.43%
0.0625 0 0.0016 0 0 0.217 0.0035 0 63.41%
0 0 0 0 0 0.19254 0.01076 0.00067 63.41%
0 0 0.0016 11 0.016 0 0 0 63.40%
0.0625 0 0 0 0.016 0 0.0035 0 63.40%
0 0 0.00261 0 0 0 0 0.00134 63.40%
0.0255 0 0.001305 0 0.00929 0 0 0.00134 63.38%
0 0 0 0 0 0.19254 0.01076 0.00134 63.38%
0 0 0.0032 0 0 0.1085 0 0.001 63.33%
0.127 0 0.0032 0 0 0 0 0 63.33%
0 0.1 0.0032 0 0 0 0.0035 0 63.31%
0.127 0 0 11 0.016 0 0 0 63.31%
0 0 0 11 0.016 0 0 0.0005 63.30%
0 0 0.00261 0 0.004645 0.19254 0 0.00134 63.30%
0 0.1 0.0032 0 0 0.1085 0 0.001 63.29%
0 0 0.0032 22 0.008 0 0.007 0 63.27%
0.051 0 0.001305 0 0.00929 0 0 0.00134 63.25%
0 0.1 0 11 0.016 0 0.0035 0 63.24%
0 0 0 0 0.008 0 0.0035 0.001 63.24% 0 0 0.0032 22 0 0 0.007 0.0005 63.23%
0.0625 0.2 0 11 0 0.217 0 0 63.23%
0 0.2 0 11 0.008 0 0 0.0005 63.22%
0.0625 0 0.0032 0 0 0 0.007 0 63.19%
0.0625 0 0.0016 22 0 0 0 0 63.19%
0.127 0 0 11 0 0.217 0.007 0 63.19%
0 0 0.0016 22 0 0.217 0 0 63.18%
0.127 0 0.0016 0 0.016 0.1085 0 0 63.16%
0.127 0.1 0 0 0 0 0 0.0005 63.16%
0 0 0 0 0.016 0 0.007 0 63.15%
0.0625 0.1 0 0 0 0.217 0 0 63.14%
0.127 0 0 0 0.016 0 0.0035 0 63.14%
0.0625 0 0.0032 0 0.008 0.1085 0 0 63.14%
0.0625 0.1 0 0 0.008 0 0.0035 0 63.13%
0 0 0.0032 0 0 0.217 0.007 0 63.12%
0 0 0 0 0 0 0.01076 0.00134 63.08%
0.0625 0 0 0 0 0 0.007 0.0005 63.06%
0.051 0 0.00261 0 0 0 0.01076 0.00134 63.05%
0 0.2 0 0 0.008 0.1085 0 0 63.04%
0 0.1 0.0032 0 0.008 0 0 0 63.03%
0 0 0.00261 0 0.00929 0 0.01076 0.00134 62.99%
0 0 0 0 0.008 0.217 0 0.0005 62.97%
0 0.2 0 11 0.008 0 0 0 62.97%
0.0625 0 0 22 0.008 0 0.0035 0 62.95%
0.0255 0 0.00261 0 0 0 0 0.00134 62.95%
0 0.2 0 22 0 0.217 0 0.001 62.92%
0 0.1 0 22 0 0 0.007 0.001 62.92%
0 0 0.0016 0 0 0 0.007 0.001 62.92%
0 0 0.0016 0 0 0 0 0.001 62.92%
0 0 0 22 0 0.217 0.007 0 62.91%
0 0.2 0 22 0 0 0.007 0.0005 62.91%
0 0.2 0 0 0.008 0 0.0035 0 62.86%
0.0625 0.2 0 0 0 0 0.0035 0 62.86%
0.0625 0 0 11 0.008 0.217 0 0 62.86%
0.127 0.1 0.0016 0 0 0 0.007 0 62.84%
0.0625 0.1 0 0 0 0 0.0035 0 62.84%
0 0 0 11 0.016 0.217 0.007 0 62.83%
0 0 0 0 0.00929 0.19254 0.00538 0.00067 62.83%
0 0 0 0 0.00929 0 0.00538 0.00134 62.82%
0.127 0 0 11 0 0.217 0.0035 0 62.81%
0 0.1 0 22 0 0 0 0.0005 62.80%
0 0 0.001305 0 0 0.19254 0.01076 0 62.80%
0.127 0.1 0 11 0.008 0 0 0 62.78%
0 0.2 0.0016 22 0 0 0.007 0 62.78% 0 0.2 0.0016 22 0 0 0 0 62.78%
0 0 0.001305 0 0.004645 0 0 0.00134 62.78%
0 0.2 0.0016 11 0.008 0 0 0 62.78%
0.0625 0 0.0032 11 0 0 0 0 62.78%
0 0 0.001305 0 0 0.19254 0.01076 0.00067 62.76%
0.127 0 0.0032 11 0.008 0 0 0 62.76%
0 0 0.001305 0 0 0.19254 0.01076 0.00134 62.73%
0.0625 0 0 0 0 0.217 0.0035 0 62.70%
0.0625 0 0 0 0.008 0.217 0 0 62.67%
0 0.1 0.0032 22 0 0 0 0.0005 62.67%
0 0 0.00261 0 0.004645 0.19254 0 0 62.65%
0.0625 0 0 0 0 0.217 0.0035 0.0005 62.65%
0.0255 0 0 0 0 0 0.01076 0.00134 62.63%
0 0.2 0 22 0 0 0 0.001 62.63%
0 0 0.0032 0 0.016 0.1085 0 0 62.60%
0 0 0 22 0.008 0.217 0.007 0 62.57%
0 0.2 0.0016 0 0 0 0.0035 0.0005 62.56%
0 0 0 0 0 0.217 0.007 0.001 62.55%
0 0 0 11 0.016 0.1085 0 0.001 62.55%
0 0 0.0032 22 0.008 0 0 0 62.54%
0 0.1 0 0 0 0 0.007 0.001 62.52%
0 0.2 0.0032 11 0 0 0 0.0005 62.52%
0 0 0.0032 0 0 0.217 0 0.0005 62.51%
0 0.2 0.0016 22 0 0 0 0.0005 62.50%
0.051 0 0.00261 0 0 0 0 0.00134 62.50%
0.0625 0.2 0 11 0 0 0.007 0 62.50%
0.127 0 0.0016 0 0 0 0.007 0.0005 62.49%
0.051 0 0 0 0.00929 0.19254 0 0 62.49%
0 0 0.0032 0 0.008 0 0.0035 0 62.46%
0.127 0.1 0.0016 0 0 0 0.0035 0 62.46%
0.127 0 0 11 0 0.217 0 0 62.42%
0.051 0 0.00261 0 0 0.19254 0.00538 0 62.39%
0.0625 0 0.0032 11 0.008 0 0 0 62.39%
0 0.2 0.0032 22 0 0 0 0 62.38%
0.0625 0.2 0 22 0 0.1085 0 0 62.36%
0.0625 0.1 0 0 0 0.217 0.007 0 62.35%
0 0.1 0.0032 0 0 0.217 0 0 62.35%
0.0625 0 0 11 0.016 0 0.007 0 62.33%
0 0.1 0 22 0.008 0 0 0.0005 62.31%
0 0 0.0032 0 0.008 0 0 0.0005 62.30%
0 0 0.001305 0 0.00929 0.19254 0.00538 0 62.30%
0.0255 0 0 0 0.00929 0 0 0.00067 62.28%
0 0 0.0032 22 0 0 0 0.0005 62.26%
0.0625 0 0 11 0 0.217 0 0 62.25% 0 0.1 0 22 0 0.217 0 0.001 62.23%
0.0255 0 0.00261 0 0 0.19254 0 0.00134 62.22%
0 0 0 0 0.016 0 0.0035 0.0005 62.19%
0 0 0 0 0.016 0.217 0.0035 0 62.19%
0 0.2 0 11 0 0 0 0.0005 62.19%
0.051 0 0 0 0 0 0.01076 0.00134 62.18%
0.0625 0 0 0 0.016 0.1085 0 0 62.18%
0 0 0 11 0.016 0.217 0 0 62.17%
0 0 0.00261 0 0 0.19254 0 0 62.15%
0.127 0 0.0016 0 0 0 0.0035 0.0005 62.11%
0 0 0.00261 0 0.00929 0 0 0.00067 62.10%
0 0.2 0.0016 11 0 0 0 0.001 62.10%
0 0.1 0 22 0.008 0.217 0 0 62.09%
0.0625 0.1 0.0016 0 0 0 0 0 62.09%
0.127 0.1 0.0016 0 0 0 0 0 62.07%
0.0625 0 0 11 0.016 0 0.0035 0 62.06%
0 0 0.00261 0 0 0 0.01076 0.00134 62.05%
0 0.2 0.0016 0 0 0.217 0.007 0 62.00%
0 0 0.0032 11 0.016 0 0 0 62.00%
0.127 0 0.0016 0 0.008 0 0 0 61.99%
0.0625 0.1 0.0032 11 0 0 0 0 61.97%
0.127 0 0.0032 11 0 0 0 0 61.95%
0 0.2 0 11 0 0 0 0.001 61.93%
0 0.1 0 0 0.008 0.217 0 0 61.92%
0.0625 0.1 0 0 0.008 0 0 0 61.92%
0.127 0 0 0 0.008 0 0 0.0005 61.91%
0 0 0 11 0.008 0.217 0 0.001 61.89%
0 0 0.0032 22 0 0.217 0 0 61.89%
0 0.2 0 0 0 0.217 0.0035 0.001 61.89%
0 0.1 0 0 0.016 0.1085 0 0 61.86%
0 0 0 11 0.016 0 0.007 0.0005 61.83%
0 0 0.0016 0 0.016 0 0 0 61.83%
0 0 0 11 0.016 0 0.007 0 61.81%
0.0625 0 0 11 0.016 0 0 0 61.80%
0 0.2 0.0032 11 0 0 0.007 0 61.79%
0.127 0 0.0032 0 0 0.1085 0 0 61.79%
0.0625 0 0 22 0 0 0.0035 0.0005 61.79%
0.127 0 0 0 0 0.1085 0.007 0.001 61.77%
0.0625 0.2 0.0016 0 0 0.1085 0 0 61.76%
0 0.1 0.0016 0 0.008 0.217 0 0 61.75%
0.127 0.1 0 11 0 0 0 0.0005 61.75%
0 0.2 0 11 0.008 0 0.007 0 61.75%
0.0625 0 0 22 0.008 0 0 0 61.74%
0.127 0 0.0016 0 0 0 0 0.0005 61.72% 0.051 0 0.00261 0 0 0.19254 0 0.00067 61.72%
0 0 0.0016 22 0 0.217 0 0.0005 61.72%
0 0 0.0016 22 0.016 0.1085 0 0 61.72%
0.0255 0 0.00261 0 0 0.19254 0 0 61.70%
0 0 0.00261 0 0 0 0.01076 0.00067 61.67%
0 0 0 22 0.008 0.217 0 0 61.66%
0 0.1 0.0016 0 0 0 0.0035 0.001 61.66%
0 0 0.0016 22 0.008 0 0 0 61.65%
0.127 0 0 0 0.016 0 0.007 0 61.63%
0 0.2 0 0 0.008 0.217 0 0 61.62%
0 0 0.0032 11 0.008 0.217 0 0 61.61%
0 0.2 0 0 0 0 0.0035 0.001 61.60%
0.0625 0.1 0.0032 0 0 0.1085 0 0 61.59%
0 0.1 0.0032 0 0 0 0.0035 0.0005 61.58%
0 0.1 0.0032 0 0 0.217 0.0035 0 61.57%
0 0 0 22 0.016 0 0.0035 0 61.56%
0 0 0.0016 22 0 0 0.0035 0.001 61.55%
0.0625 0 0.0032 0 0 0.1085 0 0 61.55%
0 0 0 22 0 0.217 0 0.001 61.54%
0.0625 0.1 0 22 0 0 0.0035 0 61.50%
0 0 0.0032 0 0 0.1085 0.0035 0.001 61.49%
0 0 0 22 0.008 0 0.007 0 61.49%
0.127 0 0 0 0 0.217 0.007 0 61.48%
0 0 0 0 0.004645 0.19254 0 0.00067 61.47%
0.0625 0 0.0016 0 0 0 0 0.0005 61.46%
0 0.1 0.0016 0 0 0 0 0.0005 61.46%
0 0.2 0 11 0 0 0.007 0 61.46%
0 0.1 0 0 0.016 0.1085 0.007 0 61.46%
0.0625 0 0.0016 11 0 0.217 0 0 61.42%
0 0 0.0016 0 0.008 0.217 0 0 61.41%
0 0 0 0 0.004645 0 0.01076 0.00134 61.40%
0 0 0 0 0 0.217 0 0.001 61.40%
0.127 0 0 0 0 0.1085 0.0035 0.001 61.38%
0 0.2 0.0016 0 0 0.217 0 0.0005 61.35%
0.127 0 0 0 0.008 0 0.0035 0.0005 61.35%
0 0 0.0016 0 0.016 0 0.007 0 61.34%
0 0.1 0 0 0.008 0 0 0.0005 61.31%
0.0625 0 0 0 0.008 0 0.007 0.0005 61.26%
0.0625 0 0.0016 0 0 0.217 0 0 61.25%
0 0.1 0 11 0.016 0 0 0 61.25%
0.0625 0 0.0016 22 0 0 0.007 0 61.25%
0.051 0 0.00261 0 0 0.19254 0 0 61.25%
0 0 0.0016 0 0 0.217 0 0.001 61.25%
0 0 0.001305 0 0 0.19254 0 0.00067 61.22% 0 0 0.00261 0 0 0 0.00538 0.00134 61.21%
0.0625 0 0 11 0 0.217 0 0.0005 61.20%
0 0 0 0 0.016 0 0.0035 0 61.17%
0.0625 0 0 0 0 0 0.007 0.001 61.14%
0 0 0 11 0 0.217 0 0.001 61.11%
0.127 0.1 0 0 0 0 0.007 0 61.10%
0.127 0 0 0 0 0.217 0.0035 0 61.10%
0.127 0 0 11 0.008 0 0 0.0005 61.09%
0 0.1 0 11 0 0 0 0.001 61.09%
0.127 0 0 0 0.016 0.1085 0 0 61.08%
0 0 0.0016 11 0 0 0 0.001 61.08%
0.127 0 0.0016 0 0 0 0.007 0 61.05%
0.0625 0 0.0032 0 0 0 0.0035 0 61.03%
0.0625 0 0 0 0.008 0 0.007 0 61.02%
0 0 0.0016 22 0 0 0 0.0005 61.01%
0.127 0 0 0 0 0.1085 0 0.001 60.99%
0 0.1 0 11 0.008 0 0 0.001 60.98%
0.0625 0 0.0016 0 0.008 0 0 0 60.97%
0 0 0.0032 11 0 0 0.0035 0.001 60.97%
0 0.2 0 11 0 0 0.007 0.001 60.96%
0.0625 0 0 22 0 0.1085 0 0 60.95%
0 0 0.0016 11 0.008 0 0 0.001 60.92%
0.127 0 0 11 0.016 0 0 0 60.92%
0.0625 0 0 0 0 0 0.0035 0.0005 60.90%
0 0.2 0 0 0 0.217 0.0035 0 60.90%
0.127 0 0.0016 11 0 0 0 0.0005 60.88%
0 0 0 0 0.00929 0 0.00538 0.00067 60.87%
0 0 0.00261 0 0.00929 0 0.00538 0.00134 60.87%
0 0.1 0 0 0 0.217 0.007 0.001 60.86%
0 0.2 0 0 0 0 0.0035 0.0005 60.85%
0 0 0 11 0.016 0.217 0.0035 0 60.85%
0.0625 0 0 11 0 0 0.007 0.001 60.85%
0 0.2 0.0016 0 0 0 0.0035 0 60.83%
0 0 0.0032 0 0 0 0.007 0.0005 60.82%
0 0.2 0.0032 11 0 0 0 0 60.82%
0.127 0 0 0 0.008 0 0.007 0.0005 60.78%
0.127 0 0 0 0.016 0 0.0035 0 60.75%
0 0 0 22 0 0 0.007 0.0005 60.74%
0 0 0.0032 22 0 0 0.0035 0 60.73%
0 0 0 0 0.008 0.1085 0 0.001 60.73%
0 0.1 0 22 0 0 0.007 0 60.73%
0.0625 0.1 0 0 0 0 0.007 0.0005 60.73%
0.127 0.1 0 0 0 0 0.0035 0 60.71%
0 0.1 0 22 0.008 0 0 0 60.71% 0 0 0.0016 0 0 0.217 0 0.0005 60.71%
0.127 0 0 11 0 0.1085 0 0.001 60.70%
0.127 0.2 0 0 0 0.1085 0.007 0 60.69%
0.0625 0.1 0 0 0 0 0 0 60.68%
0 0.2 0.0032 0 0 0.1085 0 0.0005 60.68%
0.127 0 0.0016 0 0 0 0.0035 0 60.66%
0 0.2 0.0016 11 0 0 0 0 60.65%
0.0625 0 0 22 0 0 0.007 0 60.64%
0 0.1 0 0 0.008 0 0.0035 0 60.64%
0 0 0 0 0.004645 0.19254 0.01076 0 60.63%
0 0.1 0.0032 22 0 0 0.007 0 60.59%
0 0 0.00261 0 0 0.09627 0 0.00134 60.58%
0.127 0 0 0 0 0.1085 0 0.0005 60.57%
0 0 0 0 0 0.19254 0.00538 0.00134 60.55%
0 0.1 0 22 0 0.217 0 0 60.54%
0.0625 0 0 0 0 0.217 0 0 60.54%
0.0625 0 0 0 0 0.217 0 0.0005 60.49%
0 0.2 0 22 0 0.217 0.007 0 60.47%
0 0 0.0016 22 0.008 0 0 0.0005 60.47%
0.127 0 0 11 0.008 0 0 0 60.45%
0.127 0 0.0016 11 0 0 0 0 60.44%
0 0.1 0.0032 0 0 0 0.007 0 60.41%
0.0625 0.1 0 0 0 0.1085 0 0.001 60.37%
0.127 0 0.0032 0 0 0 0.007 0 60.37%
0.0625 0.2 0 11 0 0 0.0035 0 60.34%
0 0 0.0032 22 0.008 0 0.0035 0 60.34%
0 0 0.0016 0 0.016 0.1085 0 0 60.33%
0.127 0.1 0 0 0 0 0 0 60.33%
0 0.1 0 0 0.008 0.217 0 0.0005 60.31%
0 0 0 22 0 0 0.0035 0.001 60.31%
0 0 0 0 0.008 0 0 0.001 60.30%
0.127 0.2 0 0 0 0.1085 0.0035 0 60.30%
0 0 0.001305 0 0 0.19254 0.00538 0 60.29%
0 0 0 0 0 0.19254 0 0.00134 60.29%
0 0.1 0.0016 22 0.008 0 0 0 60.29%
0 0.2 0 22 0 0 0.0035 0 60.28%
0.127 0 0.0016 0 0 0 0 0 60.28%
0.0625 0.1 0 11 0 0 0 0 60.27%
0.127 0 0 0 0.008 0 0 0 60.26%
0 0 0.0032 0 0.008 0 0.007 0 60.26%
0 0 0 0 0 0.09627 0.01076 0.00134 60.26%
0 0 0.001305 0 0.00929 0 0.01076 0.00134 60.25%
0.127 0 0 22 0 0 0.007 0 60.25%
0 0 0 0 0.008 0 0.007 0.0005 60.21% 2.67 0 0 0.00261 0 0 0.19254 0 0.00067 60.20%
0 0.0625 0.1 0 0 0 0.217 0.0035 0 60.19%
3 0 0 0 22 0 0.1085 0 0.001 60.19%
0 0.0625 0.1 0.0016 0 0 0 0.007 0 60.15%
0 0 0.2 0.0032 0 0 0.1085 0.007 0 60.14%
1.5 0.0625 0 0 0 0 0.1085 0 0.001 60.14%
0 0 0 0.0032 11 0 0.217 0 0.0005 60.13%
0 0.127 0.1 0.0016 11 0 0 0 0 60.12%
1.5 0 0 0 22 0.016 0.1085 0 0 60.12%
0 0.0625 0.2 0 0 0 0.1085 0 0.0005 60.10%
3 0 0.2 0 0 0 0 0.0035 0 60.10%
0 0 0.1 0 0 0.008 0 0.007 0.0005 60.08%
0 0 0.2 0.0016 22 0 0.217 0 0 60.07%
0 0.127 0 0.0016 0 0 0.1085 0 0.0005 60.05%
0 0.0625 0 0 0 0.008 0 0.0035 0.0005 60.05%
3 0.127 0.1 0 0 0 0.1085 0 0 60.03%
5.34 0 0 0.00261 0 0.00929 0.09627 0 0 60.03%
3 0 0 0.0032 0 0 0.217 0 0 60.01%
0 0.0255 0 0 0 0 0.19254 0.01076 0 60.00%
[0096] Next, selected combinations identified from in vitro tests are tested in a mouse model of pulmonary TB to determine optimal drug doses in vivo in the mouse model, using the PRS scheme. Drug combinations tested in vivo include the following in Table 5:
Table 5
Figure imgf000074_0001
*a Substituting OPC for EMB in Regimen II 0.77 Inhibition *b Top regimen with BDQ and OPC and without SQ.109
*c Top regimens among 9 drugs with BDQ and without PA824 and SQ109 and OPC. Inhibition 0.71 *d Top regimen (Iteration 3 with 6 drugs)
Generic Regimens to be tested include the following in Table 6:
Figure imgf000075_0001
Example 2: Fluorescence assay to determine TB inhibition
Preparation ofM. tuberculosis bacteria
[0098] These experiments utilized an M. tuberculosis Erdman inducible GFPuv strain (Mtb-iGFP) to infect human macrophages. This strain is induced to fluoresce when incubated with the inducer IPTG. To prepare the infecting inoculum, a glycerol stock of this strain was cultured on agar plates containing hygromycin (about 50 ~μg/ml) and kanamycin (about 15 μg/ml), and incubated the cultures at about 37°C, about 5% C02-95% air for 10 days.
Bacterial lawns were scraped from the agar plates into RPMl-1640 supplemented with about 20 mM FIEPES. Bacterial aggregates were dispersed by sonication of the bacterial suspension in a water bath sonicator for 8 periods of about 15 seconds, with cooling of the suspension in an ice bath for about 5 seconds in between sonications. Residual aggregates were removed by centrifugation at about 200 g for about 10 min at about 4°C. The pellet of aggregated bacteria was discarded and the supernatant suspension centrifuged again under the same conditions, and the process repeated for a total of five times. Optical density of the final suspension was measured in a spectrophotometer at about 540 nm. Bacterial numbers in the final suspension was determined according to the formula of OD540 of 0. 1 = 2 x 107 bacteria/ml. The bacteria (OD540 of 0.2) were opsonized in RPMI with about 10% human serum type AB at about 37°C for about 10 min, diluted 20-fold, and used to infect
macrophages.
Preparation of Human Macrophages [0099] Human monocytic cell line, THP-1, was grown in RPMI-1640 supplemented with about 2 mM glutamine, about 10 % heat-inactivated fetal bovine serum, and penicillin- streptomycin (about 100 U/ml and about 100 μg/ml, respectively). Prior to use in infection experiments, the THP-1 cells were spun down by centrifugation at about 200 g for about 10 min at room temperature, re-suspended in RPMI-1640 supplemented with about 2 mM glutarnine, about 10% heat-inactivated fetal bovine serum and phorbol 12-myristate 13- acetate (about 100 nM), and seeded in Matrical 96-well glass bottom plates at a density of about 1 x 105 cells/200ml/well for 3 days at about 37°C, about 5% C02-95% air atmosphere.
Testing TB Drug Combinations
[0100] Monolayers of phorbol 12-myristate 13-acetate differentiated THP-1 cells were infected for about 90 min with Mtb-iGFP at a ratio of about 10: 1, washed with RPMI, and incubated in medium with about 1 mM WTG and experimental TB drug combinations.
Included in each 96-well plate were: wells not infected with M. tuberculosis (No Infection Control); wells to which the inducer IPTG were not added (No WTG Control): and wells to which TB drugs were not added (No drug Control). All conditions were in triplicate with randomized well positions. The cultures were incubated for 4 days before fixing for one hour in about 4% paraformaldehyde in Dulbecco's Phosphate Buffered Saline (PBS). Cell nuclei were stained for about 10 min with about 1 μg/ml Hoechst 33342 in PBS containing about 0.1 % Tween 20. Monolayers were washed twice with PBS and imaged with an ImageXpress (Molecular Devices) high throughput epifluorescence microscope using a lOx objective lens. Three GFP and Hoechst epifluorescence images were acquired from non-overlapping regions of each well using FITC and DAPI filter cubes, respectively. Automated image analysis was done using the Granularity and Count Nuclei modules of MetaXpress (J'vfolecular Devices) software to quantitate the integrated GFP fluorescence intensity and the number of macrophage nuclei, respectively, for each area imaged.
Equivalents
[0101] While the disclosure has been described with reference to the specific
embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure as defined by the appended claim(s). In addition, many modifications may be made to adapt a particular situation, material, composition of matter, method, operation or operations, to the objective, spirit and scope of the disclosure. All such modifications are intended to be within the scope of the claim(s) appended hereto. In particular, while certain methods may have been described with reference to particular operations performed in a particular order, it will be understood that these operations may be combined, sub-divided, or re-ordered to form an equivalent method without departing from the teachings of the disclosure. Accordingly, unless specifically indicated herein, the order and grouping of the operations is not a limitation of the disclosure.

Claims

What is claimed is:
1. A pharmaceutical composition comprising a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises clofazimine, bedaquiline, and pyrazinamide; and wherein the drug combination optionally further comprises a pharmaceutically effective amount of one drug selected from OPC, A/C, or SQ109.
2. The pharmaceutical composition of claim 1 comprising a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises clofazimine, bedaquiline, pyrazinamide, and OPC.
3. The pharmaceutical composition of claim 1 comprising a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises clofazimine, bedaquiline, pyrazinamide, and A/C.
4. The pharmaceutical composition of claim 1 comprising a pharmaceutically effective amount of each drug in a drug combination, wherein the drug combination comprises clofazimine, bedaquiline, pyrazinamide, and SQ109.
5. A pharmaceutical composition comprising a pharmaceutically effective amount of each drug in a drug combination selected from the group consisting of drug combinations 1-176:
1 Ethambutol PA824 Rifampicin OPC
'? A/C Ethambutol Rifampicin OPC
3 Clofazimine Ethambutol Rifampicin OPC
4 A/C Ethambutol PA824 Rifampicin
5 A/C Clofazimine Ethambutol Rifampicin
6 Ethambutol ifampicin Bedaquiline OPC
7 Ethambutol PA824 Rifampicin Bedaquiline
8 Clofazimine PA824 Rifampicin OPC
9 PA824 Rifampicin SQ109 OPC
10 A/C PA824 Rifampicin OPC
1 1 A/C Ethambutol Rifampicin Bedaquiline
12 Ethambutol Rifampicin OPC
13 Clofazimine PA824 SQ109 OPC
14 Clofazimine Ethambutol Pyrazinamide Rifampicin AC Ethambutol Pyrazinamide Rifampicin
Ethambutol Pyrazinamide Rifampicin OPC
PA824 Rifampicin Bedaquiline OPC
Ethambutol PA824 Rifampicin
Clofazimine Ethambutol PA824 OPC
Clofazimine Ethambutol Rifampicin Bedaquiline
Ethambutol PA824 Rifampicin SQ109
A/C Ethambutol PA824 OPC
Clofazimine Ethambutol Rifampicin
A/C Ethambutol Rifampicin
A/C Clofazimine Rifampicin OPC
PA824 Pyrazinamide Rifampicin OPC
Clofazimine Pyrazinamide SQ109 OPC
Clofazimine Pyrazinamide Rifampicin OPC
A/C Clofazimine Ethambutol OPC
Clofazimine Rifampicin SQI 09 OPC
PA824 Pyrazinamide Rifampicin
Ethambutol
A/C Pyrazinamide Rifampicin OPC
PA824 Rifampicin OPC
A/C Clofazimine PA824 OPC
Ethambutol Rifampicin SQ109 OPC
A/C Rifampicin SQ109 OPC
A/C Clofazimine Pyrazinamide OPC
Clofazimine PA824 Pyrazinamide OPC
A/C Clofazimine Ethambutol PA824
Ethambutol Pyrazinamide Rifampicin Bedaquiline
A/C Clofazimine Ethambutol Pyrazinamide
A/C Rifampicin Bedaquiline OPC
Pyrazinamide Rifampicin SQ109 OPC
Ethambutol PA824 Bedaquiline OPC
A/C Ethambutol Rifampicin SQ109
A/C Clofazimine Pyrazinamide SQ109
Ethambutol Rifampicin Bedaquiline
A/C Clofazimine SQ109 OPC
Clofazimine Ethambutol Pyrazinamide 0
Ethambutol Pyrazinamide Rifampicin
Clofazimine Rifampicin OPC
A/C PA824 SQ109 OPC
PA824 Pyrazinamide Rifampicin SQ109
Pyrazinamide Rifampicin Bedaquiline OPC
Rifampicin SQ109 Bedaquiline OPC
Clofazimine PA824 Bedaquiline OPC A/C Rifampicin OPC
A/C Ethambutol Bedaquiline OPC
PA824 Rifampicin SQ109 Bedaquiline
A/C Clofazimine Pyrazinamide Rifampicin
Ethambutol Pyrazinamide Rifampicin SQ109
Clofazimine PA824 Pyrazinamide Rifampicin
PA824 SQ109 Bedaquiline OPC
A/C PA824 Bedaquiline OPC
PA824 Pyrazinamide SQ109 OPC
A/C Clofazimine PA824 SQ109
Clofazimine PA824 OPC
A/C PA824 Pyrazinamide OPC
A/C PA824 Rifampicin SQ109
A/C Clofazimine PA824 Rifampicin
A/C Ethambutol PA824 Bedaquiline
Clofazimine Ethambutol Bedaquiline OPC
A/C Ethambutol Pyrazinamide OPC
Clofazimine Ethambutol SQ109 OPC
Clofazimine Ethambutol OPC
A/C Clofazimine Ethambutol Bedaquiline
Ethambutol Rifampicin SQ109
Clofazimine Ethambutol PA824
Pyrazinamide Rifampicin OPC
A/C Clofazimine Ethambutol SQ109
Rifampicin SQ109 OPC
Ethambutol PA824 SQ109 OPC
A/C Clofazimine Rifampicin SQ109
Ethambutol PA824 OPC
A/C Clofazimine Ethambutol
A/C PA824 Pyrazinamide Rifampicin
Clofazimine SQ109 Bedaquiline OPC
PA824 Rifampicin SQ109
A/C Clofazimine PA824 Pyrazinamide
Clofazimine PA824 SQ109
A/C Pyrazinamide Rifampicin SQ109
Clofazimine Pyrazinamide Bedaquiline OPC
Clofazimine SQ109 OPC
A/C Rifampicin SQ109 Bedaquiline
Clofazimine PA824 Rifampicin Bedaquiline 97 A/C PA824 Rifampicin Bedaquiline
98 Ethambutol PA824 Pyrazinamide OPC
99 Clofazimine Pyrazinamide OPC
100 Clofazimine PA824 Rifampicin
101 A/C PA824 SQ109 Bedaquiline
102 Clofazimine Ethambutol Pyrazinamide
103 Rifampicin Bedaquiline OPC
104 A/C Clofazimine Bedaquiline OPC
105 A/C Ethambutol PA824 Pyrazinamide
106 PA824 Pyrazinamide Rifampicin Bedaquiline
107 Pyrazinamide Rifampicin SQ109 Bedaquiline
108 PA824 Pyrazinamide Bedaquiline OPC
109 A/C Clofazimine OPC
110 A/C Ethambutol OPC
1 11 A/C Rifampicin SQ109
112 Clofazimine Rifampicin SQ109
1 13 Clofazimine Pyrazinamide Rifampicin Bedaquiline
114 A/C Pyrazinamide SQ109 OPC
115 A/C Pyrazinamide Rifampicin Bedaquiline
116 Clofazimine Pyrazinamide Rifampicin
117 PA824 SQ109 OPC
1 18 A/C PA824 OPC
1 19 A/C Ethambutol PA824 SQ109
120 A/C PA824 Rifampicin
121 A/C Ethambutol PA824
122 A/C Pyrazinamide Bedaquiline OPC
123 A/C Ethambutol Pyrazinamide Bedaquiline
124 Clofazimine Ethambutol SQ109
125 A/C Clofazimine Pyrazinamide Bedaquiline
126 Clofazimine PA824 Pyrazinamide Bedaquiline
127 A/C Clofazimine Rifampicin Bedaquiline
128 PA824 Pyrazinamide Rifampicin
129 Pyrazinamide Rifampicin SQ109
131 A/C PA824 Pyrazinamide SQ109
132 A/C Clofazimine Rifampicin
133 A/C Clofazimine Pyrazinamide
134 A/C SQ109 Bedaquiline
135 A/C SQ109 Bedaquiline OPC
136 Clofazimine PA824 Pyrazinamide 137 A/C Pyrazinamide Rifampicin
138 PA824 Rifampicin Bedaquiline
139 A/C Clofazimine SQ109 Bedaquiline
140 Ethambutol Pyrazinamide Bedaquiline OPC
141 Ethambutol PA824 Pyrazinamide Bedaquiline
142 PA824 SQ109 Bedaquiline
143 Pyrazinamide SQ109 Bedaquiline OPC
144 A/C Clofazimine PA824 Bedaquiline
145 PA824 Bedaquiline OPC
146 Clofazimine Ethambutol Bedaquiline
147 A/C Clofazimine SQ109
148 PA824 Pyrazinamide OPC
149 Ethambutol PA824 Pyrazinamide SQ109
150 Rifampicin SQ109 Bedaquiline
15 1 Ethambutol PA824 Bedaquiline
152 A/C Clofazimine PA824
153 A/C Ethambutol Pyrazinamide SQ109
154 Ethambutol SQ109 Bedaquiline OPC
155 Ethambutol Bedaquiline OPC
156 A/C Pyrazinamide OPC
157 A/C Ethambutol Pyrazinamide
158 A/C Ethambutol SQ109 Bedaquiline
159 Ethambutol PA824 SQ109
160 Clofazimine Bedaquiline OPC
161 A/C PA824 Pyrazinamide Bedaquiline
162 A/C Ethambutol Bedaquiline
163 Clofazimine Rifampicin Bedaquiline
164 Pyrazinamide Rifampicin Bedaquiline
165 A/C Rifampicin Bedaquiline
166 A/C Bedaquiline OPC
167 Ethambutol Pyrazinamide SQ109 OPC
168 A/C Pyrazinamide SQ109 Bedaquiline
169 Ethambutol Pyrazinamide OPC
170 Ethambutol PA824 Pyrazinamide
171 A/C PA824 SQ109
172 PA824 Pyrazinamide SQ109
173 Pyrazinamide SQ109 OPC
174 A/C SQ109 OPC
175 Clofazimine PA824 Bedaquiline 176 Clofazimine Pyrazinamide Bedaquiline and
6. The pharmaceutical composition of any one of claims 1-5, wherein the drug combination does not include isoniazid (INH) and/or rifampin (RIF).
7. The pharmaceutical composition of any one of claims 1-6, further comprising one or more carriers.
8. The pharmaceutical composition of claim 5 comprising ethambutol, PA824, rifampicin and OPC in a ratio of etambutol:PA824:rifampicin:OPC of
0.2:0.0032:0.016:0.001.
9. The pharmaceutical composition of claim 5 comprising clofazimine, PA824, SQ109 and OPC in a ratio of clofazimine:PA824:SQ109:OPC of 0.127:0.0032:0.217:0.001.
10. A method to inhibit the replication of a microorganism of the group of: Mycobacterium tuberculosis Mycobacterium bovis, Mycobacterium africanum,
Mycobacterium canetti, or Mycobacterium microti, in a cell infected the microorganism, comprising contacting the cell with a pharmaceutically effective amount of the
pharmaceutical composition of any one of claims 1-9.
11. The method of claim 10, wherein the contacting is in vitro.
12. The method of claim 10, wherein the contacting is in vivo.
13. A method of treating tuberculosis (TB) in a subject in need thereof, comprising:
administering to the subject a pharmaceutically effective amount of the pharmaceutical composition of any one of claims 1-9.
14. The method of any one of claims 10-13, wherein the drug combination has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition.
15. The method of claim 13, wherein two or more drugs in the drug combination are administered sequentially.
16. The method of claim 13 or 15, wherein two or more drugs in the drug combination are administered concurrently.
17. The method of any one of claims 13, 15 and 16, wherein the subject is a mammal.
18. The method of any one of claims 13 and 15-17, wherein the subject is a human.
19. The method of any one of claims 13 and 15-18, wherein the tuberculosis (TB) is caused by Mycobacterium tuberculosis.
20. The method of any one of claims 13 and 15-18, wherein the tuberculosis (TB) is caused by a microorganism of the group of: Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, or Mycobacterium microti.
21. The method of any one of claims 13 and 15-20, wherein the tuberculosis (TB) is multi-drug resistant tuberculosis (MDR-TB).
22. The method of claim 21, wherein the MDR-TB is extensively drug-resistant tuberculosis (XDR-TB).
23. The method of any one of claims 13 and 15-222 wherein the pharmaceutical composition is administered for less than 24 months.
24. The method of any one of claims 13 and 15-23, wherein the pharmaceutically effective amount of each drug in the drug combination is independently administered once a day, twice a day or three times a day.
25. The method of any one of claims 13 and 15-24, wherein the pharmaceutical composition is administered for less than 6 months.
26. The pharmaceutical composition of any one of claims 1-9, for use in the treatment of tuberculosis (TB) in a subject in need thereof.
27. The pharmaceutical composition of claim 26, wherein the drug combination has been evaluated on the basis of in vitro treatment tests, and achieves greater than or equal to 60% projected TB inhibition.
28. The pharmaceutical composition of claim 26 or 27, wherein treatment comprises administering two or more drugs of the drug combination sequentially.
29. The pharmaceutical composition of any one of claims 26-28, wherein treatment comprises administering two or more drugs of the drug combination concurrently.
30. The pharmaceutical composition of any one of claims 26-29, wherein the subject is a mammal.
31. The pharmaceutical composition of any one of claims 26-30, wherein the subject is a human.
32. The pharmaceutical composition of any one of claims 26-31, wherein the tuberculosis (TB) is caused by Mycobacterium tuberculosis.
33. The pharmaceutical composition of any one of claims 26-31, wherein the tuberculosis (TB) is caused by Mycobacterium bovis, Mycobacterium africanum,
Mycobacterium canetti, or Mycobacterium microti.
34. The pharmaceutical composition of any one of claims 26-33, wherein the tuberculosis (TB) is multi-drug resistant tuberculosis (MDR-TB).
35. The pharmaceutical composition of claim 34, wherein the MDR-TB is extensively drug-resistant tuberculosis (XDR-TB).
36. The pharmaceutical composition of any one of claims 26-35 wherein the duration of the treatment is less than 24 months.
37. The pharmaceutical composition of any one of claims 26-36, wherein treatment comprises administering each drug of the drug combination once a day, twice a day or three times a day.
38. The pharmaceutical composition of any one of claims 26-37, wherein the duration of the treatment is less than 6 months.
39. A method of determining the optimum drug-dose of each drug in the drug combination of any one of claims 1-9, wherein the method comprises:
a) determining the optimal drug-dose combinations on the basis of in vitro studies on the efficacy of various drug-dose combinations in inhibiting Mycobacterium tuberculosis in macrophages, using a Parabolic Response Surface (PRS) optimization scheme;
b) testing optimal drug-dose combinations from a) having > 60% projected TB inhibition in a mouse model of pulmonary TB to determine the optimal drug-doses in vivo in a mouse, using the Parabolic Response Surface (PRS) optimization scheme; and
c) extrapolating a human dose from optimal drug-doses in vivo in the mouse, using drug dose extrapolation techniques and mouse and human pharmacokinetic data for the drugs.
40. The pharmaceutical composition of any one of claims 1-9 and 26-38, wherein two or more of the drugs are combined into a single solid dose formulation.
41. A kit comprising the pharmaceutical composition of any one of claims 1-9, 26-38 and 40, and instructions for use.
42. A method of treating MDR-TB in a subject in need thereof, the method comprising determining if a subject is infected with MDR-TB, and administering to the subject identified as infected with MDR-TB the pharmaceutical composition of any one of claims 1-9.
43. A method for treating MDR-TB in a subject in need thereof comprising administering the pharmaceutical composition of any one of claims 1-9 to the subject identified as being infected with MDR-TB.
44. A method of treating XDR-TB in a subject in need thereof, the method comprising determining if a subject is infected with XDR-TB, and administering to the subject identified as infected with XDR-TB the pharmaceutical composition of any one of claims 1-9.
45. A method for treating XDR-TB in a subject in need thereof comprising administering the pharmaceutical composition of any one of claims 1-9 to the subject identified as being infected with XDR-TB.
PCT/US2018/027505 2017-04-14 2018-04-13 Multi-drug therapies for tuberculosis treatment Ceased WO2018191628A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015107482A1 (en) * 2014-01-17 2015-07-23 Piramal Enterprises Limited Pharmaceutical combination for treatment of tuberculosis
WO2016073524A1 (en) * 2014-11-03 2016-05-12 The Regents Of The University Of California Multi-drug therapies for tuberculosis treatment
US20160220578A1 (en) * 2008-09-03 2016-08-04 Pfizer Inc. Combination Therapy for Tuberculosis
WO2017059411A1 (en) * 2015-10-01 2017-04-06 Memorial Sloan-Kettering Cancer Center Inhibitors of menaquinone biosynthesis

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160220578A1 (en) * 2008-09-03 2016-08-04 Pfizer Inc. Combination Therapy for Tuberculosis
WO2015107482A1 (en) * 2014-01-17 2015-07-23 Piramal Enterprises Limited Pharmaceutical combination for treatment of tuberculosis
WO2016073524A1 (en) * 2014-11-03 2016-05-12 The Regents Of The University Of California Multi-drug therapies for tuberculosis treatment
WO2017059411A1 (en) * 2015-10-01 2017-04-06 Memorial Sloan-Kettering Cancer Center Inhibitors of menaquinone biosynthesis

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