NONCLINICAL TOXICOLOGY STUDIES WITH ZIDOVUDINE - REPRODUCTIVE TOXICITY STUDIES IN RATS AND RABBITS

Zidovudine (ZDV) was evaluated for adverse effects on reproduction and fetal development in animal test species. Standard preclinical tests for reproduction and fertility, developmental toxicity, and postnatal toxicity were conducted in CD (Sprague-Dawley) fats and a developmenta l toxicity study was conducted in New Zealand white rabbits. In an add itional study, reproductive outcome was characterized in female, rats given ZDV before, during, or after mating and drug levels in the plasm a and milk of lactating rats were determined. Finally, drug exposure d ata including observed peak plasma concentrations (C-max) and area und er the concentration-time curve (AUG) were evaluated for pregnant rats and rabbits. In a reproduction/fertility study in CD rats, toxicity t o the early rat embryo, manifested as an increase in early resorptions and a decrease in litter size, was noted following dosage of the pare ntal animals with 75 or 225 mg ZDV/kg bid, A dose of 25 mg/kg bid was a no-effect level in rats. At the time of mating, male rats had been d osed for 85 days, and females had been dosed for 26 days. To further e valuate the effects of ZDV on reproduction, dosing of male rats was co ntinued to 149 days when they were mated a second time to virgin, untr eated females. Ali reproductive parameters were normal in the untreate d females from this second mating, indicating that the embryotoxic eff ect of the drug was not likely mediated by a genotoxic or other effect in the male. A separate study in female CP) rats given 225 mg/kg bid for various periods pre- or postconception suggests that the toxic eff ect of ZDV is primarily to the early rodent embryo. Early embryo death did not occur in rats or rabbits in standard developmental (teratolog y) studies; however, pregnant New Zealand white rabbits given 250 mg/k g bid during gestation Days 6-68 showed reduced weight gain, anemia, a nd an increase in late fetal deaths, No other evidence of developmenta l toxicity was noted in either species, and ZDV was not teratogenic in rats or rabbits given up to 250 mg/kg bid during the period of major organogenesis. At this dose, C values in rats and rabbits were approxi mately 234 and 150 times higher, respectively, than the mean steady-st ate serum concentration in adults following chronic oral administratio n of 250 mg every 4 hr, In both the reproduction/fertility study and a peri-and postnatal study in rats, liveborn offspring showed no advers e effects on survival, growth, or developmental measurements. (C) 1996 Society of Toxicology