EFFECT OF PREGNANCY, MODE OF ADMINISTRATION AND NEONATAL AGE ON THE PHARMACOKINETICS OF ZALCITABINE (2',3'-DIDEOXYCYTIDINE) IN THE PIGTAILED MACAQUE (MACACA-NEMESTRINA)

Our objective was to determine the effect of pregnancy, mode of admini stration and neonatal age on the pharmacokinetics of the anti-HIV drug zalcitabine (2', 3'-dideoxycytidine; ddC) in the pigtailed macaque (M acaca nemestrina). Zalcitabine was administered as an iv bolus dose to pregnant dams (n = 3) at term and at 6 weeks post-partum. No signific ant differences were found between the pre-and post-partum systemic pl asma clearance, steady-state volume of distribution or terminal plasma half-life of zalcitabine, indicating that pregnancy does not affect t he pharmacokinetics of the drug in the macaque. The observed maternal plasma, fetal plasma and amniotic fluid concentration-time profiles we re compared with profiles that were simulated using pharmacokinetic pa rameter estimates obtained in an earlier constant iv infusion study in pregnant macaques. The fetal:maternal ratio of the area under the sim ulated zalcitabine plasma concentration-time profile after an iv bolus dose (0.58) was close to the earlier observed fetal:maternal steady-s tate plasma concentration ratio after iv infusion of the drug (0.58 0.05). The excellent agreement between observed and simulated fetal:ma ternal ratio of zalcitabine demonstrates that the steady-state infusio n experimental design can be used to estimate the drug exposure to the fetus after a single dose. To determine the influence of age on the p harmacokinetics of zalcitabine, the drug was administered as a single iv bolus dose to four infant macaques serially at the ages of 1-2 week s, 1 month and 4 months. The systemic plasma clearance of zalcitabine was significantly smaller and the terminal plasma half-life significan tly longer at age 1-2 weeks than at 1 and 4 months of age. If replicat ed in humans, these substantial age-dependent changes in the pharmacok inetics of zalcitabine would warrant smaller and less frequent dosing with zalcitabine in HIV-infected neonates than in older children and a dults.