Consideration of Pharmacokinetics and Temporal Sensitivity for Hydroxyurea in Relation to Teratogenic Potential

Abstract

A compartmental pharmacokinetic-mathematical model for the time-dependent distribution of hydroxyurea (HU) in both the maternal plasma and embryonic fluids of pregnant rats and rhesus monkeys was developed. Across species scaling was based on maternal plasma clearance rates and compartmental sizes as a percent of the body weight of the dam. Mathematical optimization provided the compartmental transfer rates. The estimated maternal and embryonic concentrations of HU correlated well with the experimental pharmacokinetic data regarding both time and quantity for both the rat and the monkey. When the biological effective dose was considered to be the embryonic HU concentration over time (AUC), the dose to the individual embryos was higher in the monkeys (392 mg HU hr/L/day) than in the rats (69 mg HU hr/L/day) at an applied dose of 100 mg HU/kg administered to the dams. The AUC doses are consistent with the evaluation of the embryos of both species for teratogenic changes and embryonic death. The effect of repeated doses as compared with a single dose given only on one day of gestation was examined in the rat. Because of the rapid maternal clearance the carryover of embryonic HU concentration from one day to the next was minimal. A single treatment on Day 9 only was estimated to be sufficient to produce the adverse embryonic effects of HU on Days 9 through 12 as reported by Wilson et al. The sensitivity of the embryo to HU decreased with increasing embryonic age. The implications of the pharmacokinetic simulation and the temporal susceptibility for ongoing clinical trials of HU in the treatment of sickle cell anemia were reviewed. A human embryo dose of 69 mg HU hr/L/day was estimated to result from an i.v. dose of 10 mg/kg to the mother. This concentration produced no effect in the rat. An i.v. dose of 50 mg HU/mg was estimated to result in a human embryo dose of 353 mg HU hr/L/day which approaches a Rhesus monkey embryo dose that produced adverse effects in all embryos.

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