[go: up one dir, main page]

WO2007097991A2 - Méthodes et trousses pour administrer des agents antiviraux - Google Patents

Méthodes et trousses pour administrer des agents antiviraux Download PDF

Info

Publication number
WO2007097991A2
WO2007097991A2 PCT/US2007/004003 US2007004003W WO2007097991A2 WO 2007097991 A2 WO2007097991 A2 WO 2007097991A2 US 2007004003 W US2007004003 W US 2007004003W WO 2007097991 A2 WO2007097991 A2 WO 2007097991A2
Authority
WO
WIPO (PCT)
Prior art keywords
nucleoside
antiviral
pharmaceutically acceptable
fluoro
dideoxy
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/US2007/004003
Other languages
English (en)
Other versions
WO2007097991A3 (fr
Inventor
Susan Erickson-Viitanen
Richard Steven Levy
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.)
Gilead Pharmasset LLC
Original Assignee
Pharmasset Inc
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 Pharmasset Inc filed Critical Pharmasset Inc
Publication of WO2007097991A2 publication Critical patent/WO2007097991A2/fr
Publication of WO2007097991A3 publication Critical patent/WO2007097991A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K31/33—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine

Definitions

  • the present invention is directed to methods and pharmaceutical kits for dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in the patient, or after four to twenty-four hours, or at a time equal to or greater than the intracellular half-life of the monophosphate, diphosphate, or triphosphate form of the previously administered antiviral nucleoside.
  • HIV human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • HTV human immunodeficiency virus
  • HIV reverse transcriptase the enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA
  • Such inhibitors include antiviral nucleosides called nucleoside-based reverse transcriptase inhibitors (NRTIs) (Stein and Moore, Pharmacotherapy (2001) 21, 11-34; Erickson-Viitanen, et al., Antiviral Chemistry and Chemotherapy (2003), 14, 39-47) and antiviral nucleotides called nucleotide-based reverse transcriptase inhibitors (S.G.
  • antiviral nucleosides and monophosphprylated nucleotides are mimics of naturally occurring nucleosides or nucleotide monophosphates, containing a specific base attached to a sugar molecule. After phosphorylation to their active triphosphate forms, these antiviral nucleoside-triphosphates can compete with the endogenous pool of naturally occurring deoxynucleotide triphosphates for substrate binding to reverse transcriptase. Once incorporated into a growing chain of DNA 5 the activated antiviral nucleoside acts as a chain terminator, thereby terminating the synthesis of viral genetic material in an infected cell. In most cases, the chain termination occurs because the antiviral nucleoside lacks a 3'-hydroxyl group necessary for the attachment of the next nucleoside.
  • a wide array of antiviral nucleosides and nucleotides have been developed for treating HIV and its various mutations.
  • the various analogs differ in their ability to bind to variants of ETV that harbor mutations in the reverse transcriptase enzyme. Because each antiviral nucleoside has a different degree of specificity for any given mutant variant, the antiviral nucleoside can be carefully chosen to match the particular species of HIV in the patient. Because the swarm of viruses present in an infected patient contains many different mutant variants, it would be advantageous to administer concurrently two or more different antiviral nucleosides, where each antiviral nucleoside is tailored to target a different form of the virus.
  • antiviral nucleosides While some antiviral nucleosides can be administered concurrently, many display significant antagonism when administered together, resulting in less inhibition of viral replication than either antiviral nucleoside alone. This antagonism often results when the two antiviral nucleosides belong to the same base family, presumably because they utilize the same intracellular pathway for activation.
  • the active form of antiviral nucleosides or nucleotides is the triphosphate form.
  • a specific enzyme catalyzes activation through stepwise phosphorylation of the NRTI, first to its monophosphate form, then to diphosphate form and finally to the active triphosphate form.
  • Phosphorylation of two antiviral nucleosides from the same base family is often catalyzed by the same enzyme, which can result in antagonism where there is competition for the enzyme at some step of this process.
  • Antagonism can also presumably result from competition during cellular uptake before the occurrence of any phosphorylation.
  • zidovudine also known as ZDV or AZT
  • stavudine also known as d4T
  • Clinical studies have shown that patients taking zidovudine and stavudine together had poorer virologic responses than patients treated with zidovudine or stavudine alone.
  • In vitro experiments have also demonstrated significant antagonism for a combination of these two antiviral nucleosides (i.e., less triphosphate form produced or less antiviral effect observed for the combination than for either antiviral nucleoside alone).
  • the antagonism for the combination of zidovudine and stavudine is believed to arise because of competition for the thymidylate kinase enzyme which carries out the second phosphorylation step in the cascade.
  • the thymidylate kinase step is the rate-limiting step for zidovudine activation such that high levels of AZT-MP build up, whereas the rate-limiting step for stavudine activation is the initial production of the monophosphate (d4T-MP) carried out by thymidine kinase.
  • Thymidine kinase has a similar affinity for its natural substrate thymidine and for AZT, but d4T is a poor substrate with up to 700-fold poorer binding affinity.
  • AZT-MP acts as a substrate inhibitor of not only its own phosphorylation by thymidylate kinase, but that of d4T-MP as well, resulting in strong antagonism which can be measured in vitro. Due to this antagonism, the concurrent administration of zidovudine and stavudine is not recommended.
  • the concurrent use of two antiviral nucleosides may also be contraindicated because of inhibition of the deconstruction pathway of one of the antiviral nucleosides by the other.
  • didanosine can only be used at a low dosage when administered concurrently with tenofovir.
  • the present invention provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in the patient.
  • the present invention further provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time greater to or equal to a time selected from: i) the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, ii) the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and iii) the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • the present invention further provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered about four hours to about twenty-four hours after administration of the previously administered antiviral nucleoside.
  • the present invention further provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered about four hours to about twenty-four hours after administration of the previously administered antiviral nucleoside.
  • the present invention further provides methods of dosing a patient, which comprises: alternatively administering a therapeutically effective amount of (a) an antiviral composition comprising an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • Y is O 5 CH 2 , CHF 2 , or CF 2 ;
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted acyl, or a substituted acyl, wherein a substituent for any one of the substituted alkyl, acyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an al
  • the present invention further provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in said patient; provided that none of the administered antiviral nucleosides is an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted acyl, or a substituted acyl, wherein a substituent for any one of the substituted alkyl, acyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an alkyl
  • the present invention further provides for the use, in an alternating manner, of therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered about four hours to about twenty- four hours after administration of the previously administered antiviral nucleoside.
  • the present invention further provides the use, in an alternating manner, of therapeutically effective amount of (a) an antiviral composition comprising an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted acyl, or a substituted acyl, wherein a substituent for any one of the substituted alkyl, acyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an alkyl
  • the present invention further provides for the use, in an alternating manner, of therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in said patient; provided that none of the administered antiviral nucleosides is an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected ftom among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted acyl, or a substituted acyl, wherein a substituent for any one of the substituted alkyl, acyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an al
  • the present invention further provides variations of uses that parallel the methods of dosing.
  • the present invention further provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of the antiviral nucleoside ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fluorocytidine or pharmaceutically acceptable salt or prodrug thereof, and a further antiviral nucleoside selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, and racivir, or pharmaceutically acceptable salt or prodrug thereof, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in the patient.
  • the present invention further provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of the antiviral nucleoside ⁇ -D-2',3'-didehydro-2',3 * -dideoxy-5- fluorocytidine or pharmaceutically acceptable salt or prodrug thereof, and a further antiviral nucleoside selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, and racivir, or pharmaceutically acceptable salt or prodrug thereof, wherein each antiviral nucleoside is administered at a time greater to or equal to a time selected from: i) the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, ii) the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and iii) the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • the present invention further provides methods of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of the antiviral nucleoside ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fluorocytidine or pharmaceutically acceptable salt or prodrug thereof, and a further antiviral nucleoside selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, and racivir, or pharmaceutically acceptable salt or prodrug thereof, wherein each antiviral nucleoside is administered about four hours to about twenty- four hours after administration of the previously administered antiviral nucleoside.
  • the present invention further provides pharmaceutical kits for dosing a patient comprising:
  • the instructional material comprises an instruction to administer the antiviral nucleosides in an alternating manner such that each antiviral nucleoside is administered after the previously administered antiviral nucleoside reaches its peak plasma level.
  • the present invention further provides pharmaceutical kits comprising:
  • instructional material for the alternating administration of the antiviral nucleosides; wherein the instructional material comprises an instruction to administer each antiviral nucleoside at a time greater to or equal to a time selected from: i) the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, ii) the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and iii) the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • the present invention further provides pharmaceutical kits comprising:
  • instructional material for the alternating administration of the antiviral nucleosides; wherein the instructional material comprises an instruction to administer each antiviral nucleoside about four hours to about twenty-four hours after administration of the previously administered antiviral nucleoside.
  • the present invention provides a method of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in the patient.
  • This alternating dosing regimen allows each antiviral nucleoside to be administered at a time where the concentration of the previously administered antiviral nucleoside is lower than its peak plasma level, thereby minimizing or eliminating antagonistic interactions of the different antiviral nucleosides.
  • antiviral nucleosides As used herein, the terms “antagonism”, “antagonistic effects”, and “antagonistic interaction” refer to a detrimental clinical outcome resulting from the simultaneous administration of two or more different antiviral nucleosides as compared with the administration of each antiviral nucleoside alone. This antagonism can arise from a number of sources, including, but not limited to, competition for uptake by the cell, competition for the same activation pathway, inhibition of the enzymes responsible for activation of the other antiviral nucleoside, and inhibition of the enzymes responsible for breakdown and salvage of the other antiviral nucleosides.
  • an antiviral composition comprises an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted acyl, or a substituted acyl, wherein a substituent for any one of the substituted alkyl, acyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an alkyl
  • alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon of typically Ci to Cio, and specifically includes methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, f-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3- methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • Alkyl groups can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphorate, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected, as necessary, as known to those skilled in the art, for example, as taught in Greene et al. 1991, Protective Groups in Organic Synthesis, John Wiley & Sons, 2 nd Edition, hereby incorporated by reference.
  • lower alkyl refers to a Ci to C 4 saturated straight, branched, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group, including both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when alkyl is a suitable moiety, lower alkyl is preferred. Similarly, when alkyl or lower alkyl is a suitable moiety, unsubstituted alkyl or lower alkyl is preferred.
  • lower alkenyl refers to a C 2 to C 4 unsaturated straight or branched alkenyl group, including both substituted and unsubstituted forms. Unless otherwise specifically stated in this application, when alkenyl is a suitable moiety, lower alkenyl is preferred. Similarly, when alkenyl or lower alkenyl is a suitable moiety, unsubstituted alkenyl or lower alkenyl is preferred.
  • alkylamino or “arylamino” refer to an amino group that has one or two alkyl or aryl substituents, respectively.
  • aryl refers to phenyl, biphenyl, or naphthyl, and preferably phenyl.
  • the term includes both substituted and unsubstituted moieties.
  • the aryl group can be substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al. 1991, Protective Groups in Organic Synthesis, John Wiley & Sons, 2 nd Edition.
  • alkaryl or “alkylaryl” refer to an alkyl group with an aryl substituent.
  • aralkyl or arylalkyl refer to an aryl group with an alkyl substituent.
  • halo includes chloro, bromo, iodo and fluoro.
  • acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen CF, Cl, Br, I), Ci to C 4 alkyl or C 1 to C 4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t- butylsilyl) or
  • lower acyl refers to an acyl group in which the non-carbonyl moiety is lower alkyl.
  • nS refers to a number (0 to 5) of solvent molecules (S) that are present in a solid containing an antiviral nucleoside.
  • S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an alkyl nitrile, an aryl nitrile, an alkyl sulfoxide or sulfone, an alkyl aryl sulfoxide or sulfone, N,N- dimethylformamide, N-methylpyrrolidine, N-methylpyrrolidone, and combinations thereof; and (b) a different antiviral composition comprising at least one nucleoside or pharmaceutically acceptable salt or prodrug thereof.
  • n ranges from 0 to 4; more preferably n ranges from 0 to 3; and most preferably n ranges from 0 to 2; and very most preferably n ranges from 0 to 1.
  • S is selected from the group consisting of water, ethanol, propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, diethylether, t-butyl methyl ether, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, and combinations thereof.
  • S is selected from the group consisting of water, ethanol, propanol, butanol, acetone, ethyl acetate, diethylether, t-butyl methyl ether, and combinations thereof. Most preferably, S is selected from the group consisting of water, ethanol, propanol, butanol, and combinations thereof. Very most preferably, S is water.
  • the antiviral nucleosides would normally reach their peak plasma levels at nearly the same time, thereby maximizing any antagonistic interactions.
  • the alternating dosing method of the present invention allows the concentration of the previously administered antiviral nucleoside to subside before the next antiviral nucleoside is administered. While not wishing to be bound by any particular theory, it is theorized that this alternate dosing regimen can minimize competition for cellular uptake, as well as minimize the competition for various enzymes within the cell. It is emphasized that the invention does not require the absence of all antagonism. Instead, the clinician can choose the appropriate time to administer each antiviral nucleoside based upon the best clinical outcome for the patient.
  • the alternating administration can be accomplished by providing each antiviral nucleoside as a separate dose at separate times to the patient, such that each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level.
  • the alternating administration can also be accomplished by a suitable delayed release technique.
  • the patient could be provided with two or more different antiviral nucleosides at a single time wherein each antiviral nucleoside is released at different rates, such that each antiviral nucleoside is released at a time after the previously released antiviral nucleoside reaches its peak plasma level.
  • the alternating administration is accomplished by providing the patient with each antiviral nucleoside at a separate time, wherein each antiviral nucleoside is provided to the patient at a time after the previously administered antiviral nucleoside reaches its peak plasma level. In some embodiments, the alternating administration is accomplished by providing the patient with at least two of the antiviral nucleosides at a single time, wherein each antiviral nucleoside is released into the bloodstream of the patient at a time after the previously released antiviral nucleoside reaches its peak plasma level in the bloodstream.
  • each antiviral nucleoside is administered at a time where the previously administered antiviral nucleoside is at a fraction of its peak plasma level.
  • plasma level refers to the concentration of the antiviral nucleoside in the blood at any given time after administration of the antiviral nucleoside to the patient.
  • peak plasma level refers to the maximum concentration of the previously administered antiviral nucleoside that is reached in the blood after administration to the patient.
  • Antiviral nucleoside plasma levels can be measured by routine methods.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 75 % of its peak plasma level.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 50 % of its peak plasma level.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 25 % of its peak plasma level.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 10 % of its peak plasma level.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 5 % of its peak plasma level.
  • the present invention also allows for the administration of each antiviral nucleoside at a specific length of time after the previously administered antiviral nucleoside reaches its peak plasma level.
  • each antiviral nucleoside is administered about one hour to about one week after the previously administered antiviral nucleoside reaches its peak plasma level.
  • each antiviral nucleoside is administered about one hour to about twenty-four hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • each antiviral nucleoside is administered about one hour to about twelve hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • each antiviral nucleoside is administered about one hour to about eight hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • the present invention also allows for the administration of each, antiviral nucleoside at a specific length of time after the administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about four hours to about twenty-four hours after administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about eight hours to about eighteen hours after administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about ten hours to about fourteen hours after administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about one hour to about one month after administration of the previously administered antiviral nucleoside. In some embodiments, each antiviral nucleoside is administered at a time greater to or equal to a time selected from the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • a skilled clinician may choose between these three periods of time depending upon which step in the activation process — cellular uptake, monophosphate formation, diphosphate formation, or triphosphate formation — is rate-limiting, and thereby controls the antagonistic interaction of the two antiviral nucleosides. It is emphasized, however, that the present invention is not limited to one of these embodiments. Instead, the present invention presents a variety of other embodiments for selecting the appropriate time for administration of each antiviral nucleoside.
  • the term "intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside” refers to the time it takes for the concentration of the monophosphate form of the previously administered antiviral nucleoside to reach half of C max , wherein C m3x is the maximum observed concentration of the monophosphate form of the previously administered antiviral nucleoside in the cell.
  • the term "intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside” refers to the time it takes for the concentration of the diphosphate form of the previously administered antiviral nucleoside to reach half of Cm 8x , wherein Cmax is the maximum observed concentration of the diphosphate form of the previously administered antiviral nucleoside in the cell.
  • the term "intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside” refers to the time it takes for the concentration of the triphosphate form of the previously administered antiviral nucleoside to reach half of C ⁇ x , wherein C ma ⁇ is the maximum observed concentration of the triphosphate form of the previously administered antiviral nucleoside in the cell.
  • Intracellular half-lives can be determined by various ex vivo and in vivo methods, such as those described in P.G. Hoggard, et al., "Correlation between intracellular pharmacological activation of nucleoside analogues and HIV suppression in vitro " Antiviral Chemistry and Chemotherapy (2000), 11, 353-358 and in U.S. Patent No. 6,069,252, each of which is incorporated by reference in its entirety.
  • each antiviral nucleoside is dosed at least two times during the treatment period.
  • the method of the present invention can be used to administer at least two different antiviral nucleosides to a patient in need of treatment, hi some embodiments, the patient is in need of treatment or dosing, hi some embodiments, the patient suffers from a viral infection.
  • the viral infection is HIV.
  • the viral infection is the hepatitis B virus (HBV).
  • HBV hepatitis B virus
  • the term "HIV" refers to human immunodeficiency virus and includes all of the forms and mutations of the virus, including those forms and mutations which have yet to be discovered.
  • antiviral nucleoside refers to an analogue of a naturally occurring nucleoside or nucleotide which inhibits, directly or indirectly, the replication of a virus.
  • the antiviral nucleosides are analogues which can inhibit the HIV reverse transcriptase, the enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA.
  • the antiviral nucleosides are analogues which terminate the growth of DNA and RNA associated with HIV replication.
  • the antiviral nucleosides are nucleoside-based reverse transcriptase inhibitors (NRTIs).
  • antiviral nucleosides can compete with the endogenous pool of naturally occurring deoxynucleotide triphosphates for substrate binding to reverse transcriptase. Once incorporated into a growing chain of DNA, the activated antiviral nucleoside acts as a chain terminator, thereby terminating the synthesis of viral genetic material in an infected cell. In some embodiments, the antiviral nucleoside inhibits the replication of the hepatitis B virus (HBV).
  • HBV hepatitis B virus
  • At least two of the antiviral nucleosides utilize the same intracellular pathway.
  • intracellular pathway refers to a sequence of chemical and/or biochemical reactions leading to the formation of a new compound which takes place within a cell.
  • an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal.
  • an in vitro cell can be a cell in a cell culture.
  • an in vivo cell is a cell living in an organism such as a mammal.
  • the intracellular pathway is an activation pathway.
  • activation pathway refers to a sequence of chemical and/or biochemical reactions leading to conversion of an antiviral nucleoside to its active triphosphate form. This activation pathway involves phosphorylation of the antiviral nucleoside to its monophosphate form, followed by phosphorylation of the monophosphate to its diphosphate form, and culminating in phosphorylation of the diphosphate to its triphosphate. This activation pathway will usually involve catalysis of the phosphorylation by an enzyme. The steps for activation of certain antiviral nucleosides is summarized in Stein and Moore, Pharmacotherapy (2001) 21, 11-34, incorporated herein by reference in its entirety.
  • the activation pathway comprises phosphorylation of the antiviral nucleosides, wherein the phosphorylation is catalyzed by the same enzyme.
  • phosphorylation refers to conversion of an antiviral nucleoside to its monophosphate, diphosphate, or triphosphate form.
  • monophosphate form refers to a phosphate ester of phosphoric acid and the antiviral nucleoside.
  • diphosphate form refers to a phosphate ester of pyrophosphoric acid and the antiviral nucleoside.
  • triphosphate form refers to a phosphate ester of triphosphoric acid and the antiviral nucleoside.
  • the formation of the monophosphate, diphosphate and triphosphate forms of various antiviral nucleosides is summarized in Stein and Moore, Pharmacotherapy (2001) 21, 11-34, incorporated herein by reference in its entirety.
  • the intracellular pathway is a destruction pathway.
  • destruction refers to the process by which an antiviral nucleoside, or its monophosphate, diphosphate, or triphosphate form, is broken down, enabling salvage of its components. This process may be mediated by an enzyme.
  • a non- limiting example of destruction is the breakdown of didanosine by the enzyme, purine nucleoside phosphorylase.
  • one of the two or more different antiviral nucleosides inhibits the enzymatic degradation or salvage of another of the antiviral nucleosides.
  • enzymatic degradation refers to the chemical breakdown of an antiviral nucleoside, or its monophosphate, diphosphate, or triphosphate form, by an enzyme.
  • a non-limiting example of enzymatic degradation is the degradation of didanosine by the enzyme, purine nucleoside phosphorylase.
  • Suitable antiviral nucleosides include, but are not limited to, analogues of naturally occurring adenosine, guanosine, thymidine, or cytosine antiviral nucleosides. In some embodiments, at least two of the two or more different antiviral nucleosides are each thymidine based antiviral nucleosides. In some embodiments, at least two of the two or more different antiviral nucleosides are each guanosine based antiviral nucleosides.
  • At least two of the two or more different antiviral nucleosides are each adenosine based antiviral nucleosides. In some embodiments, at least two of the two or more different antiviral nucleosides are each cytosine based antiviral nucleosides.
  • Suitable antiviral nucleosides based on adenosine include, but are not limited to, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro- 2%3'-dideoxydidehydroadenosine, and didanosine, or pharmaceutically acceptable salts or prodrugs thereof.
  • Tenofovir disoproxil fumarate (commonly abbreviated as TDF) is an example of nucleotide which is an antiviral nucleoside. It is commercially available as Viread® from Gilead Sciences.
  • Didanosine (commonly abbreviated as ddl) is commercially available as a buffered version by the tradename Videx® from Bristol-Meyers Squibb and as a delayed release version by the tradenarae Videx® EC from Bristol-Meyers Squibb.
  • Phosphonomethoxy-2'-fluoro- 2' 5 3'-dideoxydidehydroadenosine is an experimental NRTI available from Gilead Sciences (also referred to in Cihlar, T., Ray, A., Boojamra, D., Zhang, L., Hui, H., Grant, D., White, K., Desai, M., Parkin, N. and Mackman, R.
  • GS9148 A Novel Nucleotide Active against HIV-I Vairants with Drug Resistance Mutations in Reverse Transcriptase
  • suitable antiviral nucleosides based on thymidine include, but are not limited to, zidovudine, stavudine, alovudine and dioxolane thymidine, or pharmaceutically acceptable salts or prodrugs thereof.
  • Zidovudine (commonly abbreviated as AZT) is commercially available as Retrovir® from GlaxoSmithKline and can be synthesized by the methods of U.S.
  • Stavudine (commonly abbreviated as d4T) is commercially available as Zerit® from Bristol-Meyers Squibb.
  • Alovudine is an experimental antiviral nucleoside with the code MTV -310, available from Boehringer Ingelheim (also referred to in Katlama, C, Ghosn, J., Tubiana, R., Wirden, M., Valantin, M. A., Harmenberg, J., March, G., Oberg, B., Calvez, V.
  • Dioxolane thymidine (abbreviated as DOT) is an experimental NRTI, that is available from Emory University (also referred to in Lennerstrand, J., Bluemling, G., Ruckstuhl, M., Bennett, M., Chu, C and Schinazi, R "l-( ⁇ -D-Dioxolane) Thymine is effective against HIV-I containing TAM and M184V," Abstract 46, 13 th Conference on
  • Suitable antiviral nucleosides based on guanosine include, but are not limited to, abacavir, amdoxovir, or 3 '-fluoro-2 ',3 '-dideoxy- guanosine, or pharmaceutically acceptable salts or prodrugs thereof.
  • Abacavir commonly abbreviated as ABC
  • Amdoxovir commonly abbreviated as DAPD
  • DAPD is an experimental NRTI available from RFS Pharma.
  • 3'-Fluoro-2',3'-dideoxy-guanosine is an experimental NRTI that has been described as a potent antiviral (Sjoberg, H., Wang, A., Eriksson, S., "Antiviral guanosine analogs as substrates for deoxyguanosine kinase: implications for chemotherapy," Antimicrobial Agents and Chemotherapy, 45:739-742, 2001).
  • Suitable antiviral nucleosides based on cytosine include, but are not limited to, ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine (also known as KP-1212), racivir (racemic FTC), (-)-2'-deoxy-3'-oxa-4'-thiocytidine (also known as SPD754), and ⁇ -D-5-fluoro-dioxolane-cytosine, or pharmaceutically acceptable salts or prodrugs thereof.
  • DFC ⁇ -D-2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine
  • DFC can be synthesized by the methods of U.S. Patent No. 6,927,291, incorporated herein by reference in its entirety.
  • Lamivudine (commonly abbreviated as 3TC) is commercially available as Epivir® from GlaxoSmithKline.
  • Zalcitabine (commonly abbreviated as ddC) is commercially available as Hivid® from Hoffman-La Roche.
  • Emtricitabine (commonly abbreviated as FTC) is commercially available as Emtriva® from Gilead Sciences.
  • Elvucitabine is an experimental NRTI available from Achillon Pharmaceuticals (also referred to in Ray, A.S., Murakami, E., Peterson, C.N., Shi, J., Schinazi, R.F., Anderson, K.S. "Interactions of enantiomers of 2',3'-didehydro- 2',3'-dideoxy-fiuorocytidine with wild type and Ml 84V mutant HIV-I reverse transcriptase," Antiviral Research 56:189-205, 2002).
  • Rhivir also known as racemic FTC
  • Pharmasset, Inc. also referred to in Herzmann, C, Arasteh, K., Murphy, R.L., Schulbin, H., Kreckel, P., Drauz, D., Schinazi, R.F., Beard, A., Cartee, L., Otto, M.J., "Safety, pharmacokinetics, and efficacy of ( ⁇ )-beta-2',3'-dideoxy-r-fluoro-e'-thiacytidme with efavirenz and stavudine in antiretroviral-na ⁇ ve human immunodeficiency virus- infected patients," Antimicrobial Agents and Chemotherapy 49:2828-2833, 2005).
  • KP-1212 5-Hydroxy-deoxycytidine
  • Koronis also referred to in Harris, K.S., Brabant, W., Styrchak, S., Gall, A., Daifuku, R., "KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis," Antiviral Research 67:1-9, 2005).
  • (-)-2'deoxy-3'-oxa-4 5 - thiocytidine (commonly abbreviated as (-)-dOTC, and also known as SPD754) is an experimental NRTI available from Avexa (also referred to in Taylor, D.L., Ahmed, P.S., Tyms, A.S., Wood, LJ., Kelly, L.A., Chambers, P., Clarke, J., Bedard, J., Bowlin, T.L., Rando, R.F.
  • ⁇ - D-5-Fluoro-dioxolane-cytosine is an experimental NRTI, available from RFS Pharma (also referred to in Hernandez-Santiago, B.I., Chen, H., Asif, G., Beltran, T., Mao, S., Hurwitz, SJ., Grier, J., McClure, H.M., Chu, C.K., Liotta, D.C., Schinazi, R.F., "Pharmacology and pharmacokinetics of the antiviral agent beta-D- 2',3'-dideoxy-3'-oxa-5-fluorocytidine in cells and rhesus monkeys," Antimicrobial Agents and Chemotherapy 49:2589-2597, 2005).
  • Other cytosine-based antiviral nucleosides include, but are not limited to, a
  • the term "5-carboxyamido-2',3'-dideoxy-2',3'-didehydro- pyrimidine nucleoside derivative” refers to the compounds described in U.S. Patent No. 6,232,300 and U.S. Patent No. 5,905,070, each of which is incorporated herein by reference in its entirety, as well as the 5'-alkylated, 5'-acylated, ⁇ -alkylated, and ⁇ -acylated derivatives thereof defined in U.S. Patent Nos. 6,232,300, 5,905,070, and 7,105,527, each of which is incorporated by reference in its entirety. These derivatives can be synthesized by the methods described in U.S. Patent Nos.
  • the term "5-carboxyamido-3'-modified-pyrimidine nucleoside derivative” refers to the compounds defined in U.S. Patent Nos. 6,232,300 and 5,905,070, both of which is incorporated herein by reference in their entireties, as well as the 5 '-alkylated, 5 '-acylated, ⁇ -alkylated, and N ⁇ -acylated derivatives thereof defined in U.S. Patent Nos. 6,232,300, 5,905,070, and 7,105,527, each of which is incorporated by reference in its entirety. These derivatives can be synthesized by the methods described in U.S. Patent Nos. 5,905,070, 6,391,859, and 7,105,527, each of which is incorporated by reference in its entirety.
  • the term "5-fluoro-3'-modified-pyrimidine nucleoside derivative” refers to the compounds defined in U.S. Patent No. 6,232,300 and U.S. Patent No. 5,905,070, both of which is incorporated herein by reference in their entireties, as well as the 5 '-alkylated, 5 '-acylated, N ⁇ -alkylated, and _sr*-acylated derivatives thereof defined in U.S. Patent Nos. 6,232,300, 5,905,070, and 7,105,527, each of which is incorporated by reference in its entirety. These derivatives can be synthesized by the methods described in U.S . Patent Nos. 5,905,070, 6,391 ,859, and 7,105,527, each of which is incorporated by reference in its entirety.
  • the term "pharmaceutically acceptable ester of a 5- carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative” refers to the esters disclosed in U.S. Patent Nos. 6,232,300, 5,905,070, and 6,391,859, each of which is incorporated herein by reference in its entirety, as well as the 5'-alkylated, 5'-acylated, ⁇ -alkylated, and N ⁇ acylated derivatives of the esters thereof as defined in U.S. Patent Nos. 6,232,300, 5,905,070, and 7,105,527, each of which is incorporated by reference in its entirety. These derivatives can be synthesized by the methods described in U.S. Patent Nos. 5,905,070, 6,391,859, and 7,105,527, each of which is incorporated by reference in its entirety.
  • the term "pharmaceutically acceptable ester of a 5-fluoro- 2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative” refers to the esters disclosed in U.S. Patent Nos. 6,232,300, 5,905,070, and 6,391,859, each of which is incorporated herein by reference in its entirety, as well as the 5 '-alkylated, 5'- acylated, ⁇ -alkylated, and lS ⁇ -acylated derivatives of the esters thereof as defined in U.S. Patent Nos. 6,232,300, 5,905,070, and 7,105,527, each of which is incorporated by reference in its entirety. These derivatives can be synthesized by the methods described in U.S. Patent Nos. 5,905,070, 6,391,859, and 7,105,527, each of which is incorporated by reference in its entirety.
  • the term "pharmaceutically acceptable ester of a 5- carboxyamido-3'-modified-pyrimidine nucleoside derivative” refers to the esters disclosed in U.S. Patent Nos. 6,232,300, 5,905,070, and 6,391,859, each of which is incorporated herein by reference in its entirety, as well as the 5 '-alkylated, 5'- acylated, ⁇ -alkylated, and KT'-acylated derivatives of the esters thereof as defined in U.S. Patent Nos. 6,232,300, 5,905,070, and 7,105,527, each of which is incorporated by reference in its entirety. These derivatives can be synthesized by the methods described in U.S.
  • Patent Nos. 5,905,070, 6,391,859, and 7,105,527 each of which is incorporated by reference in its entirety.
  • pharmaceutically acceptable ester of a 5-fluoro-3 '- modified-pyrimidine nucleoside derivative refers to the esters disclosed in U.S. Patent Nos. 6,232,300, 5,905,070, and 6,391,859, each of which is incorporated herein by reference in its entirety , as well as the 5'-alkylated, 5'-acylated, N 4 - alkylated, and ⁇ -acylated derivatives of the esters thereof as defined in U.S. Patent Nos. 6,232,300, 5,905,070, and 7,105,527, each of which is incorporated by reference in its entirety.
  • Each antiviral nucleoside can be administered in combination with one or more other non-antagonistic antiviral nucleosides.
  • combination medications that contain two or more different antiviral nucleosides in the same dosage unit.
  • Suitable antiviral nucleosides combinations which can be administered together include, but are not limited to Combivir® (zidovudine and lamivudine combination, available from Glaxo SmithKline), Epzicom® (abacavir and lamivudine, available from GlaxoSmithKline), Trizivir® (abacavir, zidovudine, and lamivudine, available from GlaxoSmithKline), and Truvada® (tenofovir disoproxil fumarate and emtricitabine, available from Gilead Science).
  • non-antagonistic antiviral nucleosides refers to an antiviral nucleoside that can be administered simultaneously with the other antiviral nucleoside without inducing a detrimental clinical outcome in the patient.
  • Each antiviral nucleoside can also be administered in combination with one or more antiviral agents from other drug classes, including, but not limited to, protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs), entry inhibitors (including fusion inhibitors), compounds for targeting the integration of viral DNA into the host chromosome, immune-based therapies, antisense drugs, and drugs for treating or reducing the side-effects or complications of the viral infection.
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • entry inhibitors including fusion inhibitors
  • Suitable antiviral agents that can be used in combination with the antiviral nucleosides in the methods of the invention include, but are not limited to, those listed in U.S. Patent Publication 2005/0244490 and U.S. Patent No. 7,105,527, the disclosures of which are incorporated herein by reference in their entirities.
  • Suitable NNRTIs include, but are not limited to, efavirenz (Sustiva®; available from Bristol Myers Squibb); PNU-142721; AG-1549; MKC-442 (1- (ethoxy-methyl)-5-(l-methylethyl)-6-(phenyhnethyl)-(2,4(lH,3H)-pyrimidi nedione); (+)-calanolide A (available from Sarawak Medichem); capravirine (available from Pfizer, Bristol Myers Squibb, and Tibotec-Virco Group); and nevirapine (Viramune®, available from Boeringer Ingelheim); and delavirdine (available from Pfizer).
  • efavirenz Setiva®; available from Bristol Myers Squibb
  • PNU-142721 available from Bristol Myers Squibb
  • AG-1549 MKC-442 (1- (ethoxy-methyl)-5-(l-methylethyl)-6-(phenyhneth
  • Suitable protease inhibitors include those antiviral agents that target the viral protease, an enzyme responsible for processing HIV-fusion polypeptide precursors, can be used in the present invention.
  • the proteolytic maturation of the gag and gag/pol fusion polypeptides (a process indispensable for generation of infective viral particles) has been shown to be mediated by a protease that is, itself, encoded by the pol region of the viral genome.
  • Suitable protease inhibitors include, but are not limited to saquinavir (Invirase®, available from Hoffrnann-La Roche); saquinavir (Fortovase®, available from Hoffmann-La Roche); ritonavir (Norvir®, available from Abbott Laboratories); indinavir ( ⁇ l(l,S,2R),5(S)]-2,3,5-trideoxy-N-(2,3- dihydro-2-hydroxy- lH-inden- 1 -yl)-5-[2-[[(l , 1 - di-methylethyl)amino]carbonyl]-4-
  • protease inhibitors include: GW433908 (available from GlaxoSmithKline), Tipranavir.RTM. (available from Boehringer Ingelheim); TMCl 14 (available from Tibotec Virco); ⁇ [4R-4(r-a,5-a,6-b,7-6)i-hexahydro-5,6-bis(hydroxy)-l,3-bis(3- amino)phenyl]methyl)-4,7-bis(phenylmethyl)-2H- 1 ,3 -diazepin-2-one ⁇ -bismesylate (DMP -450, available from Triangle Pharmaceuticals, Inc.); lasinavir (BMS- 234475); BMS-2322623; ABT-378; and AG-I 549.
  • DMP -450 available from Triangle Pharmaceuticals, Inc.
  • Suitable compounds for targeting the integration of viral DNA into the host chromosome include those that target integrase, the viral protein responsible for integration.
  • Suitable integrase inhibitors include, but are not limited to S- 1360 (available from Shionogi Pharmaceuticals and GlaxoSmithKline) and L-870810 (available from Merck).
  • Suitable entry inhibitors include, but are not limited to enfuvitride (Fuzeon®, available from Trimeris, AnorMED, Inc., and Progenies Pharmaceuticals); T1249 (available from Trimeris); PRO-542 (available from Progenies Pharmaceuticals); BMS 806 (available from Bristol Myers Squibb); AMD070 (available from AnorMed); and SCH C, a CCR5 antagonist that blocks the interaction between the V3 loop of gpl20 and the CCR5 receptor (available from Schering Plough).
  • enfuvitride Fuzeon®, available from Trimeris, AnorMED, Inc., and Progenies Pharmaceuticals
  • T1249 available from Trimeris
  • PRO-542 available from Progenies Pharmaceuticals
  • BMS 806 available from Bristol Myers Squibb
  • AMD070 available from AnorMed
  • SCH C a CCR5 antagonist that blocks the interaction between the V3 loop of gpl20 and the CCR5 receptor (available from Schering Plough).
  • HIV entry can be broken down into three basic steps: (1) HIV binding via the gpl20 envelope protein to the CD4 molecule on the ThI cell surface; (2) a change in envelope protein conformation that leads to gpl20 binding to a second receptor (either CCR5 or CXCR4); and 3) gp41 -mediated fusion of the viral envelope with the cell membrane, completing viral entry.
  • Suitable antisense drugs include those that block expression of viral genes using antisense oligonucleotides. Viruses are particularly suitable targets for antisense therapy because they carry genetic information distinct from the host cells. Suitable antisense drugs include, but are not limited to, HGTV43 (available from
  • Suitable immune-based therapies include, but not limited to, aldesleukin (Proleukin®, available from Chiron Corporation); HIV-I immunogen, or SaIk vaccine (Remune®, available from The Immune Response SaIk Corporation; Multikine, a mixture of several different cytokines (available from Cel-Sci Corporation); HE2000 (available from Hollis-Eden Pharmaceuticals); and
  • Cytokines are the chemical messengers of the immune system, and include small proteins and biological factors such as interleukins, chemokines, lymphokines, interferons and other signaling molecules such as tumor necrosis factor. While the role of cytokines in disease progress is not clearly understood, cytokine profiles are clearly disturbed. Levels of certain cytokines (e.g., IL-I, IL-6, TNP-alpha, inteferons-alpha and gamma) increase, while others (e.g., IL- 2) decrease.
  • cytokine therapeutic is interleukin-2 (IL-2, aldesleukin, Proleukin®, available from Chiron Corporation).
  • IL-2 interleukin-2
  • EL-2 is often used in combination with antiretroviral drugs or and during therapeutic "breaks" from antiretroviral therapy.
  • a second strategy for enhancing the immune system involves passive immunization using blood products derived from other animals or humans infected with HIV. Passive immunization has a long history in the treatment of disease beginning with the use of serum therapy in the late 1800's. Behring and Kitasato were the first to use passive immunization in the treatment of diphtheria in 1890. At that time, serum was not known to contain antibodies; rather it was only observed that serum produced a beneficial therapeutic effect. In the 1920's and 30's, sera produced in animals (e.g., horse, rabbit, sheep) was used to treat patients with measles and scarlet fever. Serum therapy declined in popularity with the discovery of antibodies, and the development of strategies such as pooling and monoclonal antibody technology.
  • HNabs heterologous neutralizing antibodies
  • heterologous refers to the source of neutralizing antibodies as "other,” and can refer to other humans or animals.
  • Li general, HNabs are prepared by purification from the serum of HIV positive individuals, or by exposing a particular animal to HTV, permitting
  • antiviral agents include, but are not limited to, hydroxyurea (Droxia®, available from Bristol-Myers Squibb); ribavirin, IL-2; IL-12; pentafuside; Yissum Project No.11607; theradigm (available from Epimmune); thymosin (Zadaxin, available from SciClone); EHT 899 (available from Enzo Biochem); HBV DNA vaccine (available from PowderJect (UK)); MCC 478 (available from Eli Lilly); interferon alfa-2b (Intron, available from Schering-Plough); adefovir dipivoxi (Hepsera, available form Gilead Sciences); Entecavir (available from Bristol-Myers Squibb); Clevudine (available from Triangle Pharmaceuticals); AM 365 (available from Amrad); telbivudine (available from Idenix); XTL 001 (a
  • Each antiviral nucleoside can also be administered with one or more agents for treating side-effects of the viral infection.
  • agents for treating these side- effects include, but are not limited to epoetin alfa (Procrit®, available from Ortho Biotech) and somatropin, or human growth hormone (Serostim®, available from Serono Laboratories).
  • Each antiviral nucleoside can also be administered with one or more other products for the treatment of complications of HIV infection and ADDS.
  • Suitable products include, but are not limited to trimetrexate glucuronate for the treatment of Pneumocystis carinii pneumonia in AIDS patients who cannot tolerate standard forms of treatment; ganciclovir for the treatment of cytomegaloviras retinitis in AIDS patients; aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in AIDS patients; erythropoietin for the treatment of zidovudine-related anemia; atovaquone for the treatment of AIDS patients with Pneumocystis carinii pneumonia who are intolerant or unresponsive to trimethoprim-sulfamethoxazole; and rifabutin for prophylaxis against Mycobacterium avium complex bacteremia in AIDS patients; vistide intravenous cidofovir for HIV-in
  • agents which can be admistered with each antiviral nucleoside in the methods of the invention include, but are not limited to, N-(I-S-
  • BM+51.0836 a triazoloiso-indolinone derivative
  • HB Y09 S-4-isopropoxycarbonyl-6-methoxy-3 -(methylthio-methy l)-3 ,4- dihydroquinoxalin-2-(lH)-thione;
  • HEPT l-[(2-hydroxy-ethoxy)methyl]6- (phenylthio)-thymine;
  • KNI-272 (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid- containing tripeptide;
  • L-735,524, hydroxyamino-pentane amide HIV-I protease inhibitor available from Mer
  • At least one antiviral nucleoside administered at a given time in the alternating dosing methods of the invention is antagonistic to at least one of the previously administered antiviral nucleosides.
  • previously administered antiviral nucleoside refers to the antiviral nucleoside administered in the administration step immediately previous to the current administration step.
  • At least two of the antiviral nucleosides are antagonistic antiviral nucleosides.
  • antagonistic antiviral nucleosides refer to two or more different antiviral nucleosides whose simultaneous administration results in a detrimental clinical outcome for the patient as compared to the outcome when each antiviral nucleoside is administered separately to the patient.
  • At least one of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, ⁇ -D-2%3'-didehydro-2',3 '-dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'- deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane-cyto
  • At least one of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof. In some embodiments, at least one of the two or more different antiviral nucleosides is selected from abacavir, amdoxovir, and 3'-fluoro-2',3'-dideoxy- guanosine; or pharmaceutically acceptable salt or prodrug thereof.
  • At least one of the two or more different antiviral nucleosides is selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'- fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof.
  • At least one of the two or more different antiviral nucleosides is selected from ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane-cytosine, a 5- carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5- fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5- carboxyamido-3'-modified-pyrimidine nucleoside derivative, or a 5-fluoro-3'- modified-pyr
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, or pharmaceutically acceptable salt or prodrug thereof.
  • At least one of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2 ' ,3 ' -dideoxy-2 ' ,3 ' -didehydro -pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3 '-modified-pyrimidine nucleoside derivative, or a 5 -fluoro-3 '-modified-pyrimidine nucleoside derivative, a pharmaceutically acceptable ester of
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2' ⁇ fluoro-2%3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fluorocytidine, zalcitabine, larnivudine, erntricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane-
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2 ⁇ 3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3'-didehydro-2 ⁇ 3'-dideoxy-5 ⁇ fluorocytidine, zalcitabine, lamivudine, erntricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine 5 ⁇ -D-5-fluoro-dioxolane-
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2%3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2%3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3'-didehydro-2 ⁇ 3'-dideoxy-5- fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cyto
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3 '-didehydro-2',3'-dideoxy-5- fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxo
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3 '- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3 '-didehydro-2',3'-dideoxy-5- fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fiuoro-d
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3 '-didehydro-2 ',3 '-dideoxy-5- fiuorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-di
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fiuoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3 '-didehydro-2',3'-dideoxy-5- fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fiuoro-d
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2 ⁇ 3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane-
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2 ⁇ 3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane-
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3 '- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fiuorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, . ⁇ -D-5-fluoro-di
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fiuoro-2',3'- dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3 '-didehydro-2',3 '-dideoxy-5- fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-di
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof, hi some embodiments, at least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 75 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 50 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 25 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 10 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 5 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about one week after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about twenty-four hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about twelve hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about eight hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, and dioxolane thymidine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time greater to or equal to a time selected from the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof. In some embodiments, at least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 75 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro ⁇ '.S'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 50 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 25 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 10 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosme; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 5 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about one week after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about twenty-four hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fiuoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about twelve hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2',3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about eight hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from abacavir, amdoxovir, and 3'- fluoro-2 ⁇ 3'-dideoxy-guanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time greater to or equal to a time selected from the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2 '-fluoro-2' ,3 '-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 75 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 50 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 25 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 10 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2 '-fluoro-2' ,3 ' -dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 5 % of its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3 * -dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about one week after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about twenty-four hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about twelve hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered about one hour to about eight hours after the previously administered antiviral nucleoside reaches its peak plasma level.
  • At least two of the two or more different antiviral nucleosides are each independently selected from tenofovir disoproxil fumarate, phos ⁇ honomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, and didanosine; or pharmaceutically acceptable salt or prodrug thereof; and each antiviral nucleoside is administered at a time greater to or equal to a time selected from the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2' ) 3 '-dideoxy-2',3 '-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3'-modified-pyrimidine nucleoside derivative, or a 5-fluor
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2 ' ,3 ' -dideoxy-2 ' ,3 '-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2%3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3 '-modif ⁇ ed-pyrimidine nucleoside derivative
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine.
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2 ' ,3 '-didehydro-2 ',3 '- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2',3 '-dideoxy-2',3 '-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2 ⁇ 3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3 '-modified-pyrimidine nucleoside derivative, or
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2 ⁇ 3 '-didehydro-2 ',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2',3 '-dideoxy-2',3 '-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3 '-modified-pyrimidine nucleoside derivative, or a 5-
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2 ⁇ 3 '-dideoxy-2',3 '-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2 ⁇ 3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3'-modified-pyrimidine nucleoside derivative, or a 5-fluoro-3'
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3 '-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3 '-modified-pyrimidine nucleoside derivative, or a 5-fluoro
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3 '-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2 ⁇ 3 '-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3 '-modified-pyrimidine nucleoside derivative, or a 5-fluoro
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2 ⁇ 3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3'-modified-pyrirnidine nucleoside derivative, or a 5-fluoro-3
  • At least two of the two or more different antiviral nucleosides are each independently selected from ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5- hydroxy-deoxycytidine, racivir, (-)-2 > -deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro- dioxolane-cytosine, a 5-carboxyamido-2 ' ,3 ' -dideoxy-2 ' ,3 ' -didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamido-3'-modified-pyrimidine nucleoside derivative,
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2 s ,3'-didehydro-2',3'-dideoxy-5-fiuorocytidine; or pharmaceutically acceptable salt or prodrug thereof; and at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, ⁇ hos ⁇ honomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-o
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2 ⁇ 3'-didehydro-2',3'-dideoxy-5-fiuorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2 ⁇ 3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2 ' -fluoro-2 ' ,3 ' -dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phos ⁇ honomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fiuoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fiuoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2 ' -fluoro-2 ',3 s -dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2 ' -fluoro-2 ' ,3 ' -dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'-o
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptahle salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fluoro-2',3'-dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-deoxy-3'--
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'-dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2 ' -fluoro-2 ' ,3 ' -dideoxydidehydroadenosine, didanosine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy-deoxycytidine, racivir, (-)-2'-
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2 ⁇ 3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2 ⁇ 3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxy
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamid
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrunidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2'
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fiuoro-2',3'-dideoxy-2',3 '-didehydro-pyrimidine nucleoside derivative,
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabme, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2 ⁇ 3'-dideoxy-2 ⁇ 3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxy
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidme; or. pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2 ⁇ 3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrirnidine nucleoside derivative, a
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamid
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2%3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carbox
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2 ⁇ 3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2 ⁇ 3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxy
  • At least one of the two or more different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine; or pharmaceutically acceptable salt or prodrug thereof; at least one other of the two or more different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thiocytidine, ⁇ -D-5-fluoro-dioxolane- cytosine, a 5-carboxyamido-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-fluoro-2',3'-dideoxy-2',3'-didehydro-pyrimidine nucleoside derivative, a 5-carboxyamid
  • the present invention also provides a method of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time greater to or equal to a time selected from: i) the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, ii) the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and iii) the intracellular half-life of the triphosphate form, of the previously administered antiviral nucleoside.
  • This method of the invention is not dependent upon the plasma level of the previously administered antiviral nucleoside. Rather, each antiviral nucleoside is administered at some time interval after the previously administered antiviral nucleoside.
  • the present invention further provides a method of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered about four hours to about twenty-four hours after administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about eight hours to about eighteen hours after administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about ten hours to about fourteen hours after administration of the previously administered antiviral nucleoside.
  • the present invention further provides a method of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of the antiviral nucleoside ⁇ -D-2',3'-didehydro-2 ⁇ 3'-dideoxy-5- fiuorocytidine or pharmaceutically acceptable salt or prodrug thereof, and a further antiviral nucleoside selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, and racivir, or pharmaceutically acceptable salt or prodrug thereof, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in the patient.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 50 % of its peak plasma level.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 25 % of its peak plasma level. In some embodiments, each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 10 % of its peak plasma level.
  • each antiviral nucleoside is administered at a time when the plasma level of the previously administered antiviral nucleoside is about 0 % to about 5 % of its peak plasma level.
  • the further antiviral nucleoside is selected from lamivudine and emtricitabine, or pharmaceutically acceptable salt or prodrug thereof.
  • the present invention further provides a method of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of the antiviral nucleoside ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fluorocytidine or pharmaceutically acceptable salt or prodrug thereof, and a further antiviral nucleoside selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, and racivir, or pharmaceutically acceptable salt or prodrug thereof, wherein each antiviral nucleoside is administered at a time greater to or equal to a time selected from: i) the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, ii) the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and iii) the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • the present invention further provides a method of dosing a patient comprising administering, in an alternating manner, therapeutically effective amounts of the antiviral nucleoside ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5- fluorocytidine or pharmaceutically acceptable salt or prodrug thereof, and a further antiviral nucleoside selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, and racivir, or pharmaceutically acceptable salt or prodrug thereof, wherein each antiviral nucleoside is administered about four hours to about twenty- four hours after administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about eight hours to about eighteen hours after administration of the previously administered antiviral nucleoside.
  • each antiviral nucleoside is administered about ten hours to about fourteen hours after administration of the previously administered antiviral nucleoside.
  • the further antiviral nucleoside is selected from lamivudine and emtricitabine, or pharmaceutically acceptable salt or prodrug thereof.
  • each method of the invention can be accomplished by providing each antiviral nucleosides as separate doses at separate times to the patient.
  • the alternating administration can also be accomplished by a suitable delayed release technique.
  • the patient could be provided with two or more different antiviral nucleosides at a single time wherein each antiviral nucleoside is released at different rates according to the embodiments of the invention.
  • a patient in a method using two antiviral nucleosides, a patient can be provided with both antiviral nucleosides at a single time, wherein the release technology is designed such that one of the antiviral nucleosides is released quickly into the blood of the patient.
  • the release technology can be designed further such that the second antiviral nucleoside is released much later at a time after the first antiviral nucleoside is released into the blood stream, according to the times specified by the methods of the invention.
  • the present invention is also directed to pharmaceutical kits for facilitating the alternating dosing methods of the inventions. Accordingly, the present invention provides a pharmaceutical kit for dosing a patient comprising:
  • instructional material for administration of the antiviral nucleosides; wherein the instructional material comprises an instruction to administer the antiviral nucleosides in an alternating manner such that each antiviral nucleoside is administered after the previously administered antiviral nucleoside reaches its peak plasma level.
  • the present invention further provides a pharmaceutical kit comprising:
  • instructional material for the alternating administration of the antiviral nucleosides; wherein the instructional material comprises an instruction to administer each antiviral nucleoside at a time greater to or equal to a time selected from: i) the intracellular half-life of the monophosphate form of the previously administered antiviral nucleoside, ii) the intracellular half-life of the diphosphate form of the previously administered antiviral nucleoside, and iii) the intracellular half-life of the triphosphate form of the previously administered antiviral nucleoside.
  • the present invention further provides a pharmaceutical kit comprising:
  • the present invention further provides for a pharmaceutical kit comprising: (a) an antiviral composition comprising an antiviral nucleoside or pharmaceutically acceptable salt thereof having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted carbonyl, or a substituted carbonyl, wherein a substituent for any one of the substituted alkyl, acyl, carbonyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an
  • the present invention also provides for a pharmaceutical kit for dosing a patient comprising (a) therapeutically effective amounts of at least two different antiviral nucleosides; provided that none of the at least two different antiviral nucleosides is an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted carbonyl, or a substituted carbonyl, wherein a substituent for any one of the substituted alkyl, acyl, carbonyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an
  • the present invention further provides for the use of a pharmaceutical kit comprising:
  • kits comprising: (a) an antiviral composition comprising an antiviral nucleoside or pharmaceutically acceptable salt thereof having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted carbonyl, or a substituted carbonyl, wherein a substituent for any one of the substituted alkyl, acyl, carbonyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an
  • the present invention also provides for the use of a pharmaceutical kit for dosing a patient comprising (a) therapeutically effective amounts of at least two different antiviral nucleosides; provided that none of the at least two different antiviral nucleosides is an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted carbonyl, or a substituted carbonyl, wherein a substituent for any one of the substituted alkyl, acyl, carbonyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an
  • the present invention further provides the use, in an alternating manner, of therapeutically effective amount of (a) an antiviral composition comprising an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted acyl, or a substituted acyl, wherein a substituent for any one of the substituted alkyl, acyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an alkyl
  • the present invention further provides for the use, in an alternating manner, of therapeutically effective amounts of two or more different antiviral nucleosides, wherein each antiviral nucleoside is administered at a time after the previously administered antiviral nucleoside reaches its peak plasma level in said patient; provided that none of the administered antiviral nucleosides is an antiviral nucleoside, or pharmaceutically acceptable salt thereof, having the following structure
  • R 1 , R 2 , R 3 , R 4 are independently selected from among hydrogen, a substituted alkyl, an unsubstituted alkyl, a substituted acyl, or an unsubstituted acyl;
  • R 5 is hydrogen, an unsubstituted phosphate, a substituted phosphate, an unsubstituted acyl, or a substituted acyl, wherein a substituent for any one of the substituted alkyl, acyl, or phosphate of R 1 , R 2 , R 3 , R 4 and R 5 is selected from the group consisting of an alkyl, an alkenyl, an alkynyl, an aryl, and combinations thereof; n is a value ranging from 0 to 5 and S is selected from the group consisting of water, an alcohol, an ether, a ketone, an alkyl acetate, an alkyl
  • the two different antiviral nucleosides are each independently selected from zidovudine, stavudine, alovudine, dioxolane thymidine, abacavir, amdoxovir, 3'-fluoro-2',3'- dideoxy-guanosine, tenofovir disoproxil fumarate, phosphonomethoxy-2'-fiuoro- 2',3'-dideoxydidehydroadenosine, didanosine, ⁇ -D-2',3'-didehydro-2',3'-dideoxy- 5-fluorocytidine, zalcitabine, lamivudine, emtricitabine, elvucitabine, 5-hydroxy- deoxycytidine, racivir, (-)-2'-deoxy-3'-oxa-4'-thio
  • one of the two different antiviral nucleosides is ⁇ -D-2',3'-didehydro-2%3'-dideoxy-5- fluorocytidine or pharmaceutically acceptable salt or prodrug thereof.
  • one of the two different antiviral nucleosides is ⁇ -D-2 ⁇ 3'-didehydro-2',3'-dideoxy-5- fluorocytidine or pharmaceutically acceptable salt or prodrug thereof and the other of the two different antiviral nucleosides is selected from zalcitabine, lamivudine, emtricitabine, elvucitabine, and racivir, or pharmaceutically acceptable salt or prodrug thereof.
  • the antiviral nucleosides are each not lamivudine. In some of the embodiments and subembodiments of the methods and kits described herein, the antiviral nucleosides are each not emtricitabine. In some of the embodiments and subembodiments of the methods and kits described herein, the antiviral nucleosides are each not stavudine.
  • the antiviral nucleosides are each not ⁇ -D-dioxolane nucleosides such as ⁇ -dioxolanylguanine, ⁇ -D-dioxolanyl-2,6-diaminopurine, and ⁇ - D-dixolanyl-6-chloropurine.
  • the antiviral nucleosides of the present invention can be provided as pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.
  • the antiviral nucleosides can also be provided as prodrugs of the antiviral nucleosides described herein.
  • prodrug refer to any covalently bonded carrier which releases the active parent antiviral nucleoside when administered to a mammalian subject.
  • Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds.
  • Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol functional groups in the antiviral nucleosides. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel
  • any of the antiviral nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside.
  • a number of nucleotide prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide.
  • substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995)1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect.
  • the antiviral nucleosides can also be provided as a 5 -phosphoether lipid or a 5 '-ether lipid, as disclosed in the following references, which are incorporated by reference herein: Kucera, L. S., N. Iyer, E. Leake, A. Raben, Modest E. K., D. L. W., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-I production and induce defective virus formation.” AIDS Res. Hum. Retro Viruses. 6:491-501; Piantadosi, C, J. Marasco C. J., S. L. Morris- Natschke, K. L. Meyer, F. Gumus, J. R. Surles, K.
  • Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside, preferably at the 5 -OH position of the nucleoside or lipophilic preparations, include U.S. Pat. Nos.
  • nucleotide prodrugs are described in the following references: Ho, D. H. W. "Distribution of Kinase and deaminase of 1-p-D- arabinofuranosylcytosine in tissues of man and muse," Cancer Res. 33, 2816-2820 (1973); Holy, “Isopolar phosphorous-modified nucleotide analogues,” in: De Clercq (ed.), Advances in Antiviral Drug Design, Vol. I, JAI Press, 179-231 (1993); Hong, C. L, Nechaev, A., and West, C. R.
  • Zidovudine also known as ZDV or AZT
  • ZDV Zidovudine
  • AZT Zidovudine
  • the antiviral nucleosides, or pharmaceutically acceptable salts or prodrugs thereof, of the present invention are administered in an amount sufficient to deliver to a patient a therapeutically effective amount of compound.
  • therapeutically effective amount refers to the amount of the antiviral nucleoside that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following:
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • the patient is administered an inhibitory amount of the antiviral nucleoside.
  • inhibitory amount refers to the amount of antiviral nucleoside which is sufficient to inhibit HIV replication in vivo, without causing serious toxic effects in the patient treated.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the antiviral nucleosides, or pharmaceutically acceptable salts or prodrugs thereof can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, transdermally, or topically, in liquid or solid form.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • the preferred mode of administration is oral.
  • a preferred dose of the antiviral nucleoside, or pharmaceutically acceptable salt or prodrug thereof, for all of the above-mentioned conditions will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day.
  • the antiviral nucleoside, or pharmaceutically acceptable salt or prodrug thereof can be conveniently administered in unit any suitable dosage form, including but not limited to one containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • a oral dosage of 50-1000 mg is usually convenient.
  • the antiviral nucleosides, or pharmaceutically acceptable salts or prodrugs thereof may be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 ⁇ M, preferably about 1.0 to 10 ⁇ M. This maybe achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the antiviral nucleoside, or pharmaceutically acceptable salt or prodrug thereof, optionally in saline, or administered as a bolus of the antiviral nucleoside, or pharmaceutically acceptable salt or prodrug thereof.
  • the antiviral nucleosides, or pharmaceutically acceptable salts or prodrugs thereof can be effective over a wide dosage range and are generally administered in therapeutically effective amounts.
  • the amount of the antiviral nucleoside actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the absorption, inactivation, and excretion rates of the drug, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the antiviral nucleoside, or pharmaceutically acceptable salt or prodrug thereof may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the antiviral nucleoside, or pharmaceutically acceptable salt or prodrug thereof can be administered as pharmaceutical compositions which contain, as the active ingredient, one or more antiviral nucleosides, or pharmaceutically acceptable salts or prodrugs thereof, in combination with one or more pharmaceutically acceptable carriers.
  • active ingredient refers to the antiviral nucleoside, or pharmaceutically acceptable salt or prodrug thereof.
  • the antiviral nucleoside is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient when it serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, syrups, wafers, chewing gum, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.
  • the active ingredient can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active ingredient is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the antiviral nucleoside is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: binders such as microcrystalline cellulose, gum tragacanth or gelatin; disintegrants such as alginic acid, Primogel, or corn starch; lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; glidants such as colloidal silicon dioxide; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents such as sucrose or saccharin; and flavoring agents such as such as peppermint, methyl salicylate, or orange flavoring.
  • the active ingredient can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the active ingredient can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, antiinflammatories, or other antivirals, including other nucleoside anti-HIV compounds.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active ingredient can be incorporated with excipients and used in the form of tablets, pills, troches, or capsules.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the active ingredient is mixed with a pharmaceutical excipient, such as those listed previously, to form a solid preformulation composition containing a homogeneous mixture of active ingredient.
  • a pharmaceutical excipient such as those listed previously
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
  • dosage unit form When the dosage unit form is a capsule, it can contain, in addition to excipients such as those listed previously, a liquid carrier such as a fatty oil.
  • the tablets and pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • Enteric formulations and compositions useful for the administration of antiviral nucleosides, or pharmaceutically acceptable salts or prodrugs thereof, as in the present invention include those disclosed in U.S. Patent Publication No. 2005/0244490, incorporated herein by reference in its entirety.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediamrinetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).
  • PBS physiological saline or phosphate buffered saline
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face masks tent, or intermittent positive pressure breathing machine, insufflator, nebuliser or a pressurised pack or other convenient means of delivering an aerosol spray.
  • Pressurised packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Liposomal suspensions are also pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
  • appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
  • aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container.
  • the container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • the active ingredients can be prepared together with carriers that will protect the compound against rapid elimination from the body, such as a controlled or sustained release formulations, including implants and microencapsulated delivery systems such that the antiviral agents may be administered in an alternating manner once inside the patient in one tablet or capsule in accordance with this invention.
  • a controlled or sustained release formulations including implants and microencapsulated delivery systems such that the antiviral agents may be administered in an alternating manner once inside the patient in one tablet or capsule in accordance with this invention.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation.
  • Tablets, caplets, or other solid dosage forms suitable for oral administration may be packaged and contained in various packaging materials particularly glass and plastic bottles and also including unit dose blister packaging.
  • the packaging material may also have labeling and information related to the pharmaceutical composition printed thereon.
  • an article of manufacture may contain a brochure, report, notice, pamphlet, or leaflet containing product information. This form of pharmaceutical information is referred to in the pharmaceutical industry as a "package insert.”
  • a package insert may be attached to or included with a pharmaceutical article of manufacture.
  • the package insert and any article of manufacture labeling provides information relating to the pharmaceutical composition.
  • the information and labeling provides various forms of information utilized by health-care professionals and patients, describing the composition, its dosage and various other parameters required by regulatory agencies such as the United States Food and Drug Agencies.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des méthodes et des trousses de médicaments pour administrer de manière alternée à un patient des nucléosides antiviraux.
PCT/US2007/004003 2006-02-16 2007-02-15 Méthodes et trousses pour administrer des agents antiviraux Ceased WO2007097991A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US77399706P 2006-02-16 2006-02-16
US60/773,997 2006-02-16

Publications (2)

Publication Number Publication Date
WO2007097991A2 true WO2007097991A2 (fr) 2007-08-30
WO2007097991A3 WO2007097991A3 (fr) 2008-06-12

Family

ID=38437868

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/004003 Ceased WO2007097991A2 (fr) 2006-02-16 2007-02-15 Méthodes et trousses pour administrer des agents antiviraux

Country Status (1)

Country Link
WO (1) WO2007097991A2 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8853171B2 (en) 2008-04-23 2014-10-07 Gilead Sciences, Inc. 1′-substituted carba-nucleoside analogs for antiviral treatment
US9090642B2 (en) 2010-07-19 2015-07-28 Gilead Sciences, Inc. Methods for the preparation of diasteromerically pure phosphoramidate prodrugs
US9724360B2 (en) 2014-10-29 2017-08-08 Gilead Sciences, Inc. Methods for treating Filoviridae virus infections
US10065958B2 (en) 2010-07-22 2018-09-04 Gilead Sciences, Inc. Methods and compounds for treating Paramyxoviridae virus infections
US10251904B2 (en) 2015-09-16 2019-04-09 Gilead Sciences, Inc. Methods for treating arenaviridae and coronaviridae virus infections
US10675296B2 (en) 2017-07-11 2020-06-09 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US10682368B2 (en) 2017-03-14 2020-06-16 Gilead Sciences, Inc. Methods of treating feline coronavirus infections
US10836787B2 (en) 2017-05-01 2020-11-17 Gilead Sciences, Inc. Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate
US10988498B2 (en) 2009-09-21 2021-04-27 Gilead Sciences, Inc. Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs
CN114010590A (zh) * 2021-11-24 2022-02-08 华东师范大学 一种核苷类抗病毒药物凝胶及其制备方法和应用
US11491169B2 (en) 2020-05-29 2022-11-08 Gilead Sciences, Inc. Remdesivir treatment methods
US11613553B2 (en) 2020-03-12 2023-03-28 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US11660307B2 (en) 2020-01-27 2023-05-30 Gilead Sciences, Inc. Methods for treating SARS CoV-2 infections
US11701372B2 (en) 2020-04-06 2023-07-18 Gilead Sciences, Inc. Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs
US11780844B2 (en) 2022-03-02 2023-10-10 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11814406B2 (en) 2020-08-27 2023-11-14 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11939347B2 (en) 2020-06-24 2024-03-26 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and uses thereof
US12357577B1 (en) 2024-02-02 2025-07-15 Gilead Sciences, Inc. Pharmaceutical formulations and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PRUVOST ET AL.: 'Measurement of Intracellular Didanosine...' ANTIMICROBIAL AGENTS AND CHEMOTHERAPY vol. 49, no. 5, 2005, pages 1907 - 1914 *
RAY ET AL.: 'Role of Purine Nucleoside Phosphorylase Interactions between 2',3'-Dideoxyinosine and Allopurinol, Ganciclovir, or Tenofovir' ANTIMICROBIAL AGENTS AND CHEMOTHERAPY vol. 48, no. 4, 2004, pages 1089 - 1095 *

Cited By (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8853171B2 (en) 2008-04-23 2014-10-07 Gilead Sciences, Inc. 1′-substituted carba-nucleoside analogs for antiviral treatment
USRE46762E1 (en) 2008-04-23 2018-03-27 Gilead Sciences, Inc 1′-substituted carba-nucleoside analogs for antiviral treatment
US10988498B2 (en) 2009-09-21 2021-04-27 Gilead Sciences, Inc. Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs
US9090642B2 (en) 2010-07-19 2015-07-28 Gilead Sciences, Inc. Methods for the preparation of diasteromerically pure phosphoramidate prodrugs
US9487544B2 (en) 2010-07-19 2016-11-08 Gilead Sciences, Inc. Methods for the preparation of diasteromerically pure phosphoramidate prodrugs
US10065958B2 (en) 2010-07-22 2018-09-04 Gilead Sciences, Inc. Methods and compounds for treating Paramyxoviridae virus infections
US11492353B2 (en) 2010-07-22 2022-11-08 Gilead Sciences, Inc. Methods and compounds for treating Paramyxoviridae virus infections
US10696679B2 (en) 2010-07-22 2020-06-30 Gilead Sciences, Inc. Methods and compounds for treating paramyxoviridae virus infections
US9949994B2 (en) 2014-10-29 2018-04-24 Gilead Sciences, Inc. Methods for treating Filoviridae virus infections
US10251898B2 (en) 2014-10-29 2019-04-09 Gilead Sciences, Inc. Methods for treating Filoviridae virus infections
US9724360B2 (en) 2014-10-29 2017-08-08 Gilead Sciences, Inc. Methods for treating Filoviridae virus infections
US11344565B2 (en) 2014-10-29 2022-05-31 Gilead Sciences, Inc. Methods for the preparation of ribosides
US10695357B2 (en) 2014-10-29 2020-06-30 Gilead Sciences, Inc. Methods for treating filoviridae virus infections
US11266666B2 (en) 2014-10-29 2022-03-08 Gilead Sciences, Inc. Methods for treating Filoviridae virus infections
US11382926B2 (en) 2015-09-16 2022-07-12 Gilead Sciences, Inc. Methods for treating Arenaviridae and Coronaviridae virus infections
US11007208B2 (en) 2015-09-16 2021-05-18 Gilead Sciences, Inc. Methods for treating arenaviridae and coronaviridae virus infections
US10695361B2 (en) 2015-09-16 2020-06-30 Gilead Sciences, Inc. Methods for treating arenaviridae and coronaviridae virus infections
US10251904B2 (en) 2015-09-16 2019-04-09 Gilead Sciences, Inc. Methods for treating arenaviridae and coronaviridae virus infections
US11260070B2 (en) 2017-03-14 2022-03-01 Gilead Sciences, Inc. Methods of treating feline coronavirus infections
US10682368B2 (en) 2017-03-14 2020-06-16 Gilead Sciences, Inc. Methods of treating feline coronavirus infections
US12030906B2 (en) 2017-05-01 2024-07-09 Gilead Sciences, Inc. Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate
US10836787B2 (en) 2017-05-01 2020-11-17 Gilead Sciences, Inc. Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate
US11597742B2 (en) 2017-05-01 2023-03-07 Gilead Sciences, Inc. Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate
US11975017B2 (en) 2017-07-11 2024-05-07 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US11266681B2 (en) 2017-07-11 2022-03-08 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US10675296B2 (en) 2017-07-11 2020-06-09 Gilead Sciences, Inc. Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections
US11660307B2 (en) 2020-01-27 2023-05-30 Gilead Sciences, Inc. Methods for treating SARS CoV-2 infections
US12012431B2 (en) 2020-03-12 2024-06-18 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US11613553B2 (en) 2020-03-12 2023-03-28 Gilead Sciences, Inc. Methods of preparing 1′-cyano nucleosides
US11701372B2 (en) 2020-04-06 2023-07-18 Gilead Sciences, Inc. Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs
US11903953B2 (en) 2020-05-29 2024-02-20 Gilead Sciences, Inc. Remdesivir treatment methods
US11975012B2 (en) 2020-05-29 2024-05-07 Gilead Sciences, Inc. Remdesivir treatment methods
US11491169B2 (en) 2020-05-29 2022-11-08 Gilead Sciences, Inc. Remdesivir treatment methods
US11939347B2 (en) 2020-06-24 2024-03-26 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and uses thereof
US12404289B2 (en) 2020-06-24 2025-09-02 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and uses thereof
US11926645B2 (en) 2020-08-27 2024-03-12 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11814406B2 (en) 2020-08-27 2023-11-14 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US12297226B2 (en) 2020-08-27 2025-05-13 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
CN114010590B (zh) * 2021-11-24 2023-12-01 华东师范大学 一种核苷类抗病毒药物凝胶及其制备方法和应用
CN114010590A (zh) * 2021-11-24 2022-02-08 华东师范大学 一种核苷类抗病毒药物凝胶及其制备方法和应用
US11851438B2 (en) 2022-03-02 2023-12-26 Gilead Sciences, Inc. 1′-cyano nucleoside analogs and methods for treatment of viral infections
US11845755B2 (en) 2022-03-02 2023-12-19 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US11780844B2 (en) 2022-03-02 2023-10-10 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US12180217B2 (en) 2022-03-02 2024-12-31 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US12448383B2 (en) 2022-03-02 2025-10-21 Gilead Sciences, Inc. Compounds and methods for treatment of viral infections
US12357577B1 (en) 2024-02-02 2025-07-15 Gilead Sciences, Inc. Pharmaceutical formulations and uses thereof

Also Published As

Publication number Publication date
WO2007097991A3 (fr) 2008-06-12

Similar Documents

Publication Publication Date Title
WO2007097991A2 (fr) Méthodes et trousses pour administrer des agents antiviraux
US6245749B1 (en) Nucleosides with anti-hepatitis B virus activity
US20250114389A1 (en) Nucleosides and nucleotides analogs as antiviral agents
US8895531B2 (en) 2′-fluoronucleoside phosphonates as antiviral agents
EP2785184B1 (fr) Compositions contenant des inhibiteurs de jak et des médicaments haart destinées à la prévention ou au traitement du vih
US20090274686A1 (en) Nucleoside phosphonate derivatives
ES2221164T3 (es) Sintesis y actividad de la inmunodeficiencia humana y antivirus de la hepatitis b de nucleosidos de 1,3-oxaselenolano.
KR20020013474A (ko) 항-ｂ형 간염 활성을 가진 뉴클레오시드
AU768059B2 (en) Beta-L-2'-deoxy-nucleosides for the treatment of HIV infection
KR20040040402A (ko) 이노신 모노포스페이트 데하이드로게나제 억제제와ｄａｐｄ의 병행 요법
EP2207553A1 (fr) Combinaisons puissantes de zidovudine et médicaments qui réalisent une sélection de la mutation k65r dans la polymérase du vih
US6410546B1 (en) Use of MKC-442 in combination with other antiviral agents
AU2003261475B2 (en) Beta-L-2'-deoxy-nucleosides for the treatment of HIV infection
AU2006246473B2 (en) Nucleosides with anti-hepatitus B virus activity
ES2349479T3 (es) Combinación farmacéutica que comprende inhibidores nucleotídicos y nucleosídicos de la transcriptasa inversa (tales como tenofovir y lamivudina) en diferentes partes de la unidad de dosificación.
AU2002258368A1 (en) DAPD combination therapy with IMDPH inhibitors such as ribavirin or mycophenolic acid
MXPA99009253A (es) Actividades anti-virus de inmunodeficiencia humana y anti-virus de hepatitis b de la sintesis de nucleosidos de 1,3-oxaselenolano

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07750815

Country of ref document: EP

Kind code of ref document: A2