Journal of Antimicrobial Chemotherapy, Vol 40, 687-693, Copyright © 1997 by The British Society for Antimicrobial Chemotherapy
T Tuntland, C Nosbisch and JD Unadkat
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.
ORIGINAL ARTICLES
Effect of pregnancy, mode of administration and neonatal age on the pharmacokinetics of zalcitabine (2', 3'-dideoxycytidine) in the pigtailed macaque (Macaca nemestrina)
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle 98195, USA.
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