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WO2004002498A1 - Regimes antiviraux - Google Patents

Regimes antiviraux Download PDF

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Publication number
WO2004002498A1
WO2004002498A1 PCT/US2003/020048 US0320048W WO2004002498A1 WO 2004002498 A1 WO2004002498 A1 WO 2004002498A1 US 0320048 W US0320048 W US 0320048W WO 2004002498 A1 WO2004002498 A1 WO 2004002498A1
Authority
WO
WIPO (PCT)
Prior art keywords
zidovudine
host
once daily
hiv
treatment
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/US2003/020048
Other languages
English (en)
Inventor
Amy Lee Keller
Dominic Joseph Vincent Paes
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.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to AU2003247646A priority Critical patent/AU2003247646A1/en
Publication of WO2004002498A1 publication Critical patent/WO2004002498A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the present invention relates to methods of treatment of HIV infections by administration of 3'-azido-3'-deoxythymidine alone or in combination with other therapeutic agents to achieve decrease in viral load and increased patience compliance.
  • 3'-Azido-3'-deoxythymidine (Retro vir ® , zidovudine) is now well established as an important and useful chemotherapeutic agent for the treatment and/or prophylaxis of HIV-infections including related clinical conditions such as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC) and also for the treatment of patients who have an asymptomatic HIV infection or who are anti-HIV antibody-positive. Treatment with zidovudine prolongs the disease-free interval in asymptomatic patients infected with HIV and delays death in symptomatic patients.
  • ARC AIDS-related complex
  • ADC AIDS dementia complex
  • the present invention addresses the issue of non-compliance by methods of treatment of HIV infections involving alternative dosing regimens.
  • the present invention features methods for the treatment of an HIV infection comprising administration of a pharmaceutically effective amount of 3'-azido-3'- deoxythymidine once daily.
  • Retrovir ® (zidovudine), also known as 3'-azido-3'-deoxythymidine, is approved for the treatment of HIV infections in combination with other antiretro viral agents. It is also indicated for the prevention of maternal-fetal HIV transmission as part of a regiment that includes oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and administration of zidovudine syrup to the neonate after birth.
  • Retrovir ® The recommended oral dose of Retrovir ® is 600 mg per day in divided doses in combination with other antiretroviral agents.
  • the recommended dose in pediatric patients 6 weeks to 12 years of age is 160 mg/m 2 every 8 hours in combination with other antiretroviral agents.
  • Zidovudine is rapidly absorbed and distributed, with peak serum concentrations occurring within 0.5 and 1.5 hours. Elimination is rapid with terminal half-life of approximately 1.5 - 2 hours. It is renally eliminated by hepatic metabolism. It was originally thought that the intracellular half-life of the active metabolite, zidovudine triphosphate, would not be adequate to provide sufficient levels of the drug to achieve a therapeutic effect upon administration of the drug in a once daily regimen compared with 300 mg twice daily administration. However, we have recently discovered that, surprisingly, administration of zidovudine once daily is sufficient to provide a therapeutic effect.
  • the present invention features methods for the treatment of an HIV infection in a host, for example, a mammal, for example, a human, comprising administering to said host a therapeutically effective amount of 3'-azido-3'- deoxythymidine, or a pharmaceutically acceptable derivative thereof, once daily.
  • Preferred esters in accordance with the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, n-propyl, t-butyl, or n- butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C alkyl, or C alkoxy), or amino; (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L- isoleucyl); and (4) phosphonate esters.
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
  • terapéuticaally effective amount means a sufficient amount of a drug, compound, composition, product or pharmaceutical agent to abate or reverse or treat a malady in a human or other mammal without severely harming the tissues of the mammal to which the drug or pharmaceutical agent is administered.
  • treatment extends to both the prophylaxis and the treatment of an established malady, infection or its symptoms. It will be appreciated that zidovudine may exist in the keto or enol tautomeric form and the use of such a tautomeric form is within the scope of this invention.
  • Zidovudine can be prepared, for example, as described in U.S. Patent 4,724,232, incorporated herein by reference hereto. Zidovudine can also be obtained from Aldrich Chemical Co., Milwaukee, WI 53233, USA.
  • Zidovudine or its pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of HIV infection or conditions associated with HIV infection or AIDS.
  • Such combination therapies according to the present invention comprise the administration of zidovudine or a pharmaceutically acceptable derivative thereof with at least one other pharmaceutically active ingredient.
  • the active ingredient(s) and pharmaceutically active agents may be administered simultaneously in either the same or different pharmaceutical compositions or sequentially in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the combination therapy involves the administration of zidovudine and another therapeutic agent selected from [[[2- (6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2- dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), [[(lR)-2-(6- amino-9H-purin-9-yl)-l-methylethoxy]methyl]phosphonic acid (tenofovir), and (R)-[[2-(6-Amino-9H-purin-9-yl)- 1 -methylethoxy]methyl]phosphonic acid bis- (isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA), hydroxyurea, 2',3'- dideoxycytidine (ddC, zalcitabine), 2',3'-dideoxyadenosine, 2',3'-dideoxyinosine (ddl,
  • the therapeutic agent to be combined with zidovudine for once daily administration is selected from (-)-cis-l-(2-hydroxymethyl)-l,3- oxathiolane 5-yl)-cytosine (lamivudine), (-)-cis-4-[2-amino-6- (cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-l-methanol (abacavir), 2',3'- dideoxyinosine (ddl, didanosine), efavirenz (DMP 266), nevirapine, and tenofovir.
  • the present invention further features a method for the prevention or treatment of an HIV infection in host, for example, a mammal, for example, a human, comprising once daily administration of zidovudine and another therapeutic agent selected from (-)-cis- 1 -(2-hydroxymethyl)- 1 ,3 -oxathiolane 5- yl)-cytosine (lamivudine), or a pharmaceutically acceptable derivative of lamivudine, and (-)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2- cyclopentene-1-methanol (abacavir), or a pharmaceutically acceptable derivative of abacavir.
  • Particularly suitable are methods according to the present invention comprising once daily administration of zidovudine and lamivudine.
  • Other suitable methods according to the present invention comprise once daily administration of zidovudine, lamivudine and abacavir.
  • phrases "pharmaceutically acceptable derivative of abacavir” as used herein, means any pharmaceutically acceptable salt, solvate, ester, or salt of such ester, of abacavir, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) abacavir or any antivirally active metabolite or residue thereof.
  • lamivudine means any pharmaceutically acceptable salt, solvate, ester, or salt of such ester, of lamivudine, or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) lamivudine or any antivirally active metabolite or residue thereof.
  • lamivudine is provided substantially free of the corresponding (+)- enantiomer.
  • substantially free means that there is less than about 10% w/w of the (+)-enantiomer present compared with the amount of lamivudine.
  • the methods of the present invention conveniently allow administration of two or more drugs in unit dosage form containing, for example, from about 10 to

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des procédés de traitement d'infections par VIH par administration de 3'-azido-3'-désoxythymidine (zidovudine) dans des régimes posologiques alternatifs, de préférence une fois par jour.
PCT/US2003/020048 2002-06-27 2003-06-25 Regimes antiviraux Ceased WO2004002498A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003247646A AU2003247646A1 (en) 2002-06-27 2003-06-25 Antiviral regimens

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US39267002P 2002-06-27 2002-06-27
US60/392,670 2002-06-27

Publications (1)

Publication Number Publication Date
WO2004002498A1 true WO2004002498A1 (fr) 2004-01-08

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PCT/US2003/020048 Ceased WO2004002498A1 (fr) 2002-06-27 2003-06-25 Regimes antiviraux

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AU (1) AU2003247646A1 (fr)
WO (1) WO2004002498A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006001029A3 (fr) * 2004-06-25 2006-05-11 Hetero Drugs Ltd Compositions antiretrovirales
WO2006086865A3 (fr) * 2005-02-21 2006-12-28 Fundacao Oswaldo Cruz Composition pharmaceutique, processus de preparation de cette composition, utilisation de cette composition dans le traitement de l'immunodeficience causee par une infection par le vih et technique de traitement associee
AU2007212583B2 (en) * 2006-02-03 2012-12-06 The Government of the United States of America, as represented by the Secretary Department of Health and Human Services, Centers for Disease Control and Prevention Inhibition of HIV infection through chemoprophylaxis

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0284405A2 (fr) * 1987-03-27 1988-09-28 Baker Norton Pharmaceuticals, Inc. Composés antiviraux, formes d'administration et méthodes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0284405A2 (fr) * 1987-03-27 1988-09-28 Baker Norton Pharmaceuticals, Inc. Composés antiviraux, formes d'administration et méthodes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ADKINS J C ET AL: "Efavirenz", DRUGS 1998 NEW ZEALAND, vol. 56, no. 6, 1998, pages 1055 - 1064, XP009019609, ISSN: 0012-6667 *
DAAR E S ET AL: "Improving adherence to antiretroviral therapy", AIDS READER 01 FEB 2003 UNITED STATES, vol. 13, no. 2, 1 February 2003 (2003-02-01), pages 81 - 90, XP009020052, ISSN: 1053-0894 *
ROSENBACH K A ET AL: "Daily dosing of highly active antiretroviral therapy", CLINICAL INFECTIOUS DISEASES 01 MAR 2002 UNITED STATES, vol. 34, no. 5, 1 March 2002 (2002-03-01), pages 686 - 692, XP009019702, ISSN: 1058-4838 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006001029A3 (fr) * 2004-06-25 2006-05-11 Hetero Drugs Ltd Compositions antiretrovirales
WO2006086865A3 (fr) * 2005-02-21 2006-12-28 Fundacao Oswaldo Cruz Composition pharmaceutique, processus de preparation de cette composition, utilisation de cette composition dans le traitement de l'immunodeficience causee par une infection par le vih et technique de traitement associee
AU2007212583B2 (en) * 2006-02-03 2012-12-06 The Government of the United States of America, as represented by the Secretary Department of Health and Human Services, Centers for Disease Control and Prevention Inhibition of HIV infection through chemoprophylaxis
US9044509B2 (en) * 2006-02-03 2015-06-02 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibition of HIV infection through chemoprophylaxis
US9579333B2 (en) 2006-02-03 2017-02-28 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibition of HIV infection through chemoprophyalxis
US9937191B2 (en) 2006-02-03 2018-04-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibition of HIV infection through chemoprophylaxis
US10335423B2 (en) 2006-02-03 2019-07-02 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibition of HIV infection through chemoprophylaxis

Also Published As

Publication number Publication date
AU2003247646A1 (en) 2004-01-19

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