Implications of the kinetics of zidovudine in the pregnant baboon following oral administration

Zidovudine (ZDV) therapy in pregnancy reduces mother-to-child transmission of HIV. The action of ZDV in the fetus is thought to be an important contri butor to efficacy. Previous research in primates has demonstrated that cont inuous infusion of ZDV to the mother leads to sustained plasma concentratio ns in the fetus; however, it has not been determined what concentrations of ZDV are achieved in the fetus following oral administration. The pharmacok inetics of drug distribution to the fetus following oral administration of a 100-mg dose of ZDV to the mother are reported from 6 chronically catheter ized baboons. The first order elimination half-life of ZDV from both the mo ther and fetus was approximately 1.2 hours. The area under the concentratio n-time curve for the fetus was 77% (r(2) = 0.98; p <.001) that of the mothe r and the estimated peak drug levels in the fetus were 52% (r(2) = 0.83; p <.01) those in the mother. The rapid transfer and short half-life of ZDV le ads to a drug concentration-time profile that would not sustain levels in t he fetus with dosing every 4 hours. After comparing these findings with exi sting data from pregnant and nonpregnant humans, it seems likely that curre nt dose recommendations for ZDV in pregnancy would not maintain levels of t he active intracellular metabolite of ZDV in all fetuses. This may explain in part the 8% failure rate of ZDV prophylaxis. The correlation between fet al and maternal plasma concentrations of ZDV would allow titration of dose based on maternal drug levels to achieve fetal levels within the therapeuti c range.