Evaluation of subchronic (13 weeks) and reproductive toxicity potential ofintravaginal 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 fo r 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 preven ting HIV transmission as well as providing fertility control, we previously identified novel phenyl phosphate derivatives of 3'-azido-3'-deoxythymidin e (zidovudine) which exhibit potent anti-HIV and spermicidal activities. Th is study reports the preliminary preclinical study of our lead compound WHI -05, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-methoxyphenyl) m ethoxyalaninyl phosphate, for use as a dual-function topical microbicide. A cute toxicity studies have shown that WHI-05 has no detectable adverse effe cts on laboratory animals. The 13-week subchronic and reproductive toxicity potential of intravaginal gel-microemulsion formulation of WHI-05 were stu died in mice to support its further development as a virucidal spermicide. Groups of 10 female B6C3F1 mice were exposed intravaginally to a gel-microe mulsion 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 intrava ginal treatment, one half of treated mice were evaluated for toxicity and t he other half were mated with untreated males to Evaluate potential reprodu ctive and developmental effects. Repetitive intra vaginal application of WH I-05 to yield a local concentration 6.1 x 10(4) times higher than its in vi tro HIV IC50 value and 1200 times higher than its spermicidal EC50 value di d not cause weight loss, morbidity, mortality, or specific tissue lesions d etectable by histopathology. Furthermore, repeated intravaginal exposure of mice to WHI-05 for 13 weeks had no adverse effects on subsequent reproduct ive performance (100% fertile), neonatal survival (>96%), or pup developmen t. These findings collectively show that the experimental dual-function ant i-HIV and contraceptive agent, WHI-05, did not cause significant acute or s ubchronic and reproductive toxicity under the test conditions CONTRACEPTION 2000;61:69-76 (C) 2000 Elsevier Science Inc. All rights reserved.