Lack of adverse effects on fertility of female CD-1 mice exposed to repetitive intravaginal gel-microemulsion formulation of a dual-function anti-HIVagent: Aryl phosphate derivative of bromo-methoxy-zidovudine (compound WHI-07)

5-bromo-6-methoxy-5,6-dihydro-3 ' -azidothymidine-5 '-(p-bromophenyl) metho xyalaninyl phosphate (WHI-07), a novel bromo-methoxy-substituted aryl phosp hate derivative of zidovudine (ZDV), is a potent dual-function contraceptiv e agent with anti-HIV activity. Its potential for reproductive toxicity was assessed in a series of experiments using CD-1 mice under the conditions o f its intended use as an intravaginal microbicide. Female CD-1 mice were ex posed intravaginally to a gel-microemulsion formulation containing 0%, 0.5% , 1.0% or 2.0% WHI-07 for up to 13 weeks. On a molar basis, these concentra tions represent 1400-5700 times its in vitro spermicidal IC50 and 1.4-5.7 ( x 10(6)) times its in vitro anti-HIV IC50. We examined the effects of intra vaginally administered WHI-07 on: ovulation efficiency; in vivo fertilizati on and early embryonic, fetal development; and reproductive outcome, includ ing neonatal survival and pup development. Compound WHI-07 was administered intravaginally during superovulation, organogenesis and prior to mating fo r 5 and 10 consecutive days and for 13 weeks, respectively. Mice were evalu ated for ovulation efficiency and fertilization rate and cleavage 14 and 40 h after human chorionic gonadotropin (hCG) injection, respectively. Pregna nt mice were administered 2% WHI-07 intravaginally during gestation days (G D) 6-15 and measures of teratogenicity were evaluated on GD 17. For short-t erm toxicity study, mice were given intravaginal treatment of gel-microemul sion containing 0%, 0.5%, 1.0% and 2.0% WHI-07 for 13 weeks and then mated with untreated males to evaluate potential reproductive and developmental e ffects. Repeated intravaginal exposure of mice to 2% WHI-07 had no adverse effects on ovulation response, mean number of eggs recovered or the percent age of eggs fertilized or cleaved. No evidence of reproductive toxicity, fe tal toxicity or teratogenicity was found following repetitive intravaginal application of 2% WHI-07 during the period of organogenesis. Furthermore, r epeated intravaginal exposure of mice to 0.5-2.0% WHI-07 for 13 weeks had n o adverse effect on the subsequent reproductive capability, perinatal outco me or growth and development of the offspring. Compound WHI-07 shows unique clinical potential as a safe, dual-function vaginal contraceptive for curb ing mucosal and perinatal HIV transmission. Copyright (C) 2001 John Wiley & Sons, Ltd.