Evaluation of subchronic (13 weeks) and reproductive toxicity potential of intravaginal gel-microemulsion formulation of a dual-function phenyl phosphate derivative of bromo-methoxy zidovudine (compound WHI-05) in B6C3F1 mice

Heterosexual transmission of human immunodeficiency virus (HIV) accounts for 90% of all new infections worldwide and significantly contributes to new acquired immunodeficiency syndrome (AIDS) cases in the United States. In a systematic effort to develop a microbicidal contraceptive capable of preventing HIV transmission as well as providing fertility control, we previously identified novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidine (zidovudine) which exhibit potent anti-HIV and spermicidal activities. This study reports the preliminary preclinical study of our lead compound WHI-05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) methoxyalaninyl phosphate, for use as a dual-function topical microbicide. Acute toxicity studies have shown that WHI-05 has no detectable adverse effects on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were studied in mice to support its further development as a virucidal spermicide. Groups of 10 female B6C3F1 mice were exposed intravaginally to a gel-microemulsion formulation containing 0%, 0.5%, 1.0%, or 2.0% WHI-05, 5 days/week for 13 consecutive weeks. On a molar basis, these concentrations represent 300 to 1200 times their in vitro spermicidal potency, and 1.5 x 10(4) to 6.1 x 10(4) times their in vitro anti-HIV activity. After 13 weeks of intravaginal treatment, one half of treated mice were evaluated for toxicity and the other half were mated with untreated males to Evaluate potential reproductive and developmental effects. Repetitive intra vaginal application of WHI-05 to yield a local concentration 6.1 x 10(4) times higher than its in vitro HIV IC50 value and 1200 times higher than its spermicidal EC50 value did not cause weight loss, morbidity, mortality, or specific tissue lesions detectable by histopathology. Furthermore, repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproductive performance (100% fertile), neonatal survival (>96%), or pup development. These findings collectively show that the experimental dual-function anti-HIV and contraceptive agent, WHI-05, did not cause significant acute or subchronic and reproductive toxicity under the test conditions CONTRACEPTION 2000;61:69-76 (C) 2000 Elsevier Science Inc. All rights reserved.