racivir and HIV-Infections

Several new nucleoside analogs are currently in development for the treatment of HIV-1 infections. Alovudine, amdoxovir, elvucitabine, Racivir, Reverset and SPD 754 are nucleoside reverse transcriptase inhibitors that were designed and selected in anticipation of having improved resistance, safety, compatibility and efficacy profiles. Clinical trials are demonstrating that some of these goals are being met, and that nucleoside analogs as a class of compounds remain fertile ground for finding valuable additions to current anti-retrovirus treatment regimens.

Topics: Animals; Anti-HIV Agents; Clinical Trials as Topic; Cytidine Triphosphate; Deoxycytidine; Dideoxynucleosides; Dioxolanes; Emtricitabine; HIV Infections; Humans; Purine Nucleosides; Reverse Transcriptase Inhibitors; Thionucleosides; Zalcitabine

Racivir is a 50:50 racemic mixture of the (-)- and (+)-beta-enantiomers of 2'-deoxy-3'-thia-5-fluorocytosine (FTC), which is being developed for the treatment of HIV and hepatitis B virus (HBV). The (+)-enantiomer of FTC is approximately 10-20-fold less potent than (-)-FTC, but it selects for a different HIV mutation in human lymphocytes. Plasma concentrations from a group of 54 rats, 12 pregnant rabbits and 60 dogs enrolled in large toxicity studies using a wide variety of oral doses, were compared using non-compartment pharmacokinetic modelling versus dose, treatment duration, species and gender. The pharmacokinetics of Racivir were also compared with those of a previously published pharmacokinetic study in rhesus monkeys and with data from HIV-infected human male volunteers. The (+)-FTC, but not the (-)-enantiomer, can be deaminated to the non-toxic inactive metabolite (+)-FTU. Therefore, the plasma exposure to (+)-FTU was also determined. The order of relative plasma exposure to (+)-FTU was rhesus monkeys > humans > pregnant rabbits > dogs > rats. Allometric scaling was performed to relate systemic clearance/fraction of drug absorbed (Cl/F) and terminal phase volume of distribution (Vbeta/F) versus species body weights. No individual animal species mimicked the Cl/F values in humans. However, allometric scaling using a combination of rats, pregnant rabbits and monkeys predicted the mean human Cl/F value better than a combination of rats and rabbits only (within 0.24 and SD of mean vs 0.81 SD of the observed mean value). Similarly, human Vbeta/F values were best predicted using a combination of rat and monkey data (within 0.64 SD of mean value). Species demonstrating greater deamination to (+)-FTU tended to have greater than predicted Cl/F values. The Cmax values of dogs were the closest to humans, but were statistically different. This study highlights the importance of selecting animal species that demonstrate similar cytidine deaminase activity to humans when performing preclinical dosing studies on Racivir and other antiviral agents that are substrates for mammalian cytidine deaminases.

Topics: Animals; Antiviral Agents; Dogs; Emtricitabine; Female; HIV Infections; Humans; Macaca mulatta; Male; Pregnancy; Rabbits; Rats; Rats, Sprague-Dawley; Species Specificity; Zalcitabine

Racivir [RCV; (+/-)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine], a 50:50 racemic mixture of the two beta nucleoside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in combination with stavudine and efavirenz to HIV-1-infected treatment-naïve male volunteers in a phase Ib/IIa study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in all dosage groups, with mean reductions from 1.13 to 1.42 log10 by day 4 and 2.02 to 2.43 log10 by day 14. HIV RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean viral loads ranging from 2.1 to 2.6 log10 below baseline through day 28. By day 35, HIV RNA levels began to increase but still remained >1 log10 below baseline levels.

Topics: Administration, Oral; Adult; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Emtricitabine; HIV Infections; HIV-1; Humans; Middle Aged; Oxazines; Plasma; Reverse Transcriptase Inhibitors; RNA, Viral; Stavudine; Urine; Zalcitabine