The
zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5'-(p-bromophenyl) methoxy alaninyl
phosphate (WHI-07), is a dual-function spermicidal and
anti-HIV agent with
contraceptive and microbicidal activity. In previous subchronic and reproductive toxicity studies and a two-year carcinogenicity study, daily intravaginal application of 0.5 to 2.0%
WHI-07 via a gel-microemulsion, was shown to cause no local, systemic and reproductive toxicity or increased carcinogenicity in mice. To evaluate the developmental toxicity potential of
WHI-07 in a nonrodent model, subgroups of 20 superovulated NZW rabbits were artificially inseminated and exposed intravaginally to a gel-microemulsion containing 0, 0.5, 1.0, or 2.0%
WHI-07 during major organogenesis [gestation days 6-18]. The dose of
WHI-07 was equivalent to 1.4x10(6) to 5.7x10(6) times its anti-HIV IC50 and 1400 to 5700 times its spermicidal EC50. Throughout the duration of the experiment (GD 0-29), clinical observations, food consumption, and
body weights were recorded. Reproductive and fetal parameters were evaluated following uterotomies on GD 29. Measurements included numbers of corpora lutea, pregnancy, number and distribution of implantations, resorptions, live and dead fetuses,
fetal weight, sex ratio, and gross external and skeletal malformations and variations. Maternal food consumption and
body weight gain were unaffected by
WHI-07 treatment. Hematologic and clinical chemistry determinations on GD 19 and 29 revealed no treatment-related maternal effects. Prior studies of repeated
intravaginal administration of
WHI-07 gel-microemulsion revealed lack of local toxicity to rabbit vaginal mucosa. In the current study, no
drug-related gross lesions were apparent at necropsy. Reproductive indices, ie, pregnancy rate, gravid uterine weights, litter size, number of corpora lutea, implantation sites, pre- and postimplantation losses, viable fetuses,
resorptions, fetal body weights, and fetal sex ratio, were not affected by intravaginal exposure to
WHI-07. External, and skeletal examinations of fetuses for malformations and variations did not reveal any evidence of teratogenicity in any WHI-07-treated groups.
Intravaginal administration of
WHI-07 at concentrations as high
as 2% did not produce teratogenicity or other developmental toxicity in rabbit conceptus. These findings indicated that
WHI-07 shows unique clinical potential to become the active ingredient of a new female-controlled topical microbicidal vaginal
contraceptive for women who are at high risk of acquiring HIV/
AIDS.