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 administration and neonatal age on the pharmacokinetics of the anti-HIV drug zalcitabine (2',3'-dideoxycytidine; ddC) in the pigtailed macaque (Macaca nemestrina). Zalcitabine was administered as an i.v. bolus dose to pregnant dams (n = 3) at term and at 6 weeks post-partum. No significant differences were found between the pre- and post-partum systemic plasma clearance, steady-state volume of distribution or terminal plasma half-life of zalcitabine, indicating that pregnancy does not affect the pharmacokinetics of the drug in the macaque. The observed maternal plasma, fetal plasma and amniotic fluid concentration-time profiles were compared with profiles that were simulated using pharmacokinetic parameter estimates obtained in an earlier constant i.v. infusion study in pregnant macaques. The fetal:maternal ratio of the area under the simulated zalcitabine plasma concentration-time profile after an i.v. bolus dose (0.58) was close to the earlier observed fetal:maternal steady-state plasma concentration ratio after i.v. infusion of the drug (0.58 +/- 0.05). The excellent agreement between observed and simulated fetal:maternal ratio of zalcitabine demonstrates that the steady-state infusion 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 pharmacokinetics of zalcitabine, the drug was administered as a single i.v. bolus dose to four infant macaques serially at the ages of 1-2 weeks, 1 month and 4 months. The systemic plasma clearance of zalcitabine was significantly smaller and the terminal plasma half-life significantly longer at age 1-2 weeks than at 1 and 4 months of age. If replicated in humans, these substantial age-dependent changes in the pharmacokinetics of zalcitabine would warrant smaller and less frequent dosing with zalcitabine in HIV-infected neonates than in older children and adults.
Tuntland
T
T
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195, USA.
Nosbisch
C
C
Unadkat
J D
JD
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D000983:Antipyrine / Q000493:pharmacokinetics; D019540:Area Under Curve; D005260:Female; D006207:Half-Life; D008254:Macaca nemestrina; D008954:Models, Biological; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D016047:Zalcitabine / Q000008:administration & dosage / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016047:Zalcitabine; D000983:Antipyrine