Resistance to abacavir has developed in laboratory versions of HIV which are also resistant to other HIV-specific antiretrovirals such as lamivudine , didanosine , and zalcitabine. HIV strains that are resistant to protease inhibitors are not likely to be resistant to abacavir. Abacavir is contraindicated for use in infants under 3 months of age. Little is known about the effects of Abacavir overdose. Overdose victims should be taken to a hospital emergency room for treatment.
The prevalence of the allele is estimated to be 3. In African Americans , the prevalence is estimated to be 1. It will be appreciated that tenofovir DF and emtricitabine, and their physiologically functional derivatives may exist in keto or enol tautomeric forms and the use of any tautomeric form thereof is within the scope of this invention. A large number of structurally-diverse prodrugs have been described for phosphonic acids Freeman and Ross in Progress in Medicinal Chemistry A commonly used prodrug class is the acyloxyalkyl ester, which was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al J.
Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester strategy, the alkoxycarbonyloxyalkyl ester, may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability DeLambert et al J.
Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described Khamnei andTorrence, J. Benzyl esters are reported to generate the parent phosphonic acid.
In some cases, substituents at the ortho- or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e. Examples of this class of prodrugs are described by Mitchell et al J.
Perkin Trans. Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide.
Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide Puech et al Antiviral Res. Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds. Prodrug esters in accordance with the invention are independently selected from the following groups: 1 mono-, di-, and tri-phosphate esters of tenofovir or emtricitabine or any other compound which upon administration to a human subject is capable of providing directly or indirectly said mono-, di, or triphosphate ester; 2 carboxylic acid esters 3 sulphonate esters, such as alkyl- or aralkylsulphonyl for example, methanesulphonyl ; 4 amino acid esters for example, alanine, L-valyl or L- isoleucyl ; 5 phosphonate; and 6 phosphonamidate esters.
An exemplary aryl moiety present in such esters comprises a phenyl or substituted phenyl group. Many phosphate prodrug moieties are described in US Patent No. Retro Viruses ; Piantadosi et al J. Agents Chemother. Pharmaceutically acceptable prodrugs refer to a compound that is metabolized in the host, for example hydrolyzed or oxidized, by either enzymatic action or by general acid or base solvolysis, to form an active ingredient.
Typical examples of prodrugs of the active ingredients of the combinations of the invention have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, esterified, deesterified, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated, or other functional group change or conversion involving forming or breaking chemical bonds on the prodrug.
The active ingredients, tenofovir disoproxil fumarate and emtricitabine, in the pharmaceutical formulations of the invention have relatively low pKa values, indicative of the potential to cause acidic hydrolysis of the active ingredients. Emtricitabine, with a pKa of 2. Tenofovir disoproxil fumarate, with a pKa of 3. It is desirable to formulate a therapeutic combination of tenofovir disoproxil fumarate and emtricitabine, and the physiological functional derivatives thereof, with a minimum of impurities and adequate stability.
The combinations of the present invention provide combination pharmaceutical dosage forms which are chemically stable to acid degradation of: 1 a first component such as tenofovir disoproxil fumarate, and physiological functional derivatives; 2 a second component such. Exemplary third active ingredients to be administered in combination with first and second components are shown in Table A. SALTS Any reference to any of the compounds in the compositions of the invention also includes any physiologically acceptable salt thereof.
Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
For therapeutic use, salts of active ingredients of the combinations of the invention will be physiologically acceptable, i. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.
A two-part or three-part combination may be administered simultaneously or sequentially. When administered sequentially, the combination may be administered in one, two, or three administrations. Preferably, two-part or three-part combinations are administered in a single pharmaceutical dosage form. More preferably, a two-part combination is administered as a single oral dosage form and a three-part combination is administered as two identical oral dosage forms.
Examples include a single tablet of tenofovir disoproxil fumarate and emtricitabine, or two tablets of tenofovir disoproxil fumarate, emtricitabine, and efavirenz.
It will be appreciated that the compounds of the combination may be administered: 1 simultaneously by combination of the compounds in a co-formulation or 2 by alternation, i. In alternation therapy, the delay in administering the second, and optionally a third active ingredient, should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients.
By either method of administration 1 or 2 , ideally the combination should be administered to achieve peak plasma concentrations of each of the active ingredients. A one pill once-per-day regimen by administration of a combination co- formulation may be feasible for some HIV-positive patients. Effective peak plasma concentrations of the active ingredients of the combination will be in the range of approximately 0.
Optimal peak plasma concentrations may be achieved by a formulation and dosing regimen prescribed for a particular patient. It will also be understood that tenofovir DF and emtricitabine, or the physiologically functional derivatives of either thereof, whether presented simultaneously or sequentially, may be administered individually, in multiples, or in any combination thereof.
In general, during alternation therapy 2 , an effective dosage of each compound is administered serially, where in co-formulation therapy 1 , effective dosages of two or more compounds are administered together. The references hereinafter to formulations refer unless otherwise stated to formulations containing either the combination or a component compound thereof.
It will be understood that the administration of the combination of the invention by means of a single patient pack, or patient packs of each formulation, within a package insert diverting the patient to the correct use of the invention is a desirable additional feature of this invention. The invention also includes a double pack comprising in association for separate administration, formulations of tenofovir disoproxil fumarate and emtricitabine, or a physiologically functional derivative of either or both thereof.
The combination therapies of the invention include: 1 a combination of tenofovir DF and emtricitabine or 2 a combination containing a physiologically functional derivative of either or both thereof. The combination may be formulated in a unit dosage formulation comprising a fixed amount of each active pharmaceutical ingredient for a periodic, e.
The most common treatment-related adverse events are diarrhea , headache , nausea , and rash. Among the more severe side effects patients may experience are a hepatotoxicity or a lactic acidosis.
Mechanism of action[ edit ] Emtricitabine is an analogue of cytidine. Both of these changes are associated with healthier immune systems and decreased likelihood of serious illness.
It can inhibit both types 1 and 2 of HIV reverse transcriptase and also the reverse transcriptase of hepatitis B virus. It is phosphorylated to active metabolites that compete for incorporation into viral DNA. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.
Some research suggests that lamivudine can cross the blood—brain barrier. Lamivudine is often given in combination with zidovudine , with which it is highly synergistic.The chemical names for Tenofovir disoproxil include: [2- 6-amino-purinyl -l- methyl-ethoxymethylj-phosphonic acid diisopropoxycarbonyloxymethyl ester; 9-[ R [[bis[[ isopropoxycarbonyl oxy]methoxy]phosphinyl]methoxy]propyl]adenine; and 2,4,6, 8-tetraoxaphosphanonanedioic acid, 5-[[ lR 6-amino-9H-purinyl -l- methylethoxy]methyl]-, bis l-methylethyl ester, 5-oxide. Thus, FTC may be either a cis or a trans isomer or mixtures thereof. Lamivudine treatment has been shown to restore zidovudine sensitivity of previously resistant HIV. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e. Parker, Ed. The combinations include at least one active ingredient selected from 1 tenofovir disoproxil fumarate and physiologically functional derivatives, and at least one active ingredient selected from 2 emtricitabine and physiologically functional derivatives.
Diastereomers have different physical properties, e. As noted above, formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For example, the invention includes physiological functional derivatives such as the racemic mixture of the enantiomers 2R, 55, cis amino fluoro-l- 2-hydroxymethyl-l,3-oxathiolanyl - lH -pyrimidinone emtricitabine and its mirror image 25, 5R, cis aminofluoro-l- 2-hydroxymethyl-l,3-oxathiolan- 5-yl - lH -pyrimidinone, or mixtures of the two enantiomers in any relative amount. Lamivudine is often given in combination with zidovudine , with which it is highly synergistic.
Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
Table A. For therapeutic use, salts of active ingredients of the combinations of the invention will be physiologically acceptable, i. The safety profile of emtricitabine during treatment is similar to that of a placebo.
Raymond F. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. The term "chemical stability" means that the two primary antiviral agents in combination are substantially stable to chemical degradation. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l- yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2-naphthylethen-l-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
Solution and tablet have comparable concentrations and bioavailability. Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. When tenofovir is coadministered with didanosine, the concentration of didanosine increases, and may lead to didanosine toxicity which may result in complications such as pancreatitis and neuropathy. US Patent Nos. An exemplary aryl moiety present in such esters comprises a phenyl or substituted phenyl group.
These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. In one embodiment, each compound will be employed in the combination in an amount at which it exhibits antiviral activity when used alone. The aqueous solutions should be suitably buffered preferably to a pH of from 3 to 9 , if necessary. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
Lower doses predict better patient compliance when pill burden decreases, dosing schedules are simplified and, optionally, if synergy between compounds occurs Loveday, C. Human immunodeficiency virus type 1 HIV-1 protease Prt is essential for viral replication and is an effective target for approved antiviral drugs. History[ edit ] Emtricitabine was discovered by Dr.