Comparative Pharmacokinetics of Racivir®,(±)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine in Rats,Rabbits,Dogs,Monkeys and HIV-Infected Humans

Racivir® is a 50:50 racemic mixture of the (–)- and (+)-β-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 (V_β/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 V_β/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 C_max 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® other antiviral agents that are substrates for mammalian cytidine deaminases.