Pharmacokinetics and topical vaginal effects of two tenofovir gels in rabbits

Tenofovir (TFV) 1% gel has proven effective in preclinical and clinical studies in preventing sexual transmission of HIV-1. The impact of changing the current gel formulation to reduce its osmolality was evaluated using pharmacokinetic assessments and local tissue effects in the rabbit. Following vaginal administration of TFV 1% gel and reduced-glycerin TFV 1% gel, TFV was measured in plasma, vaginal tissues, vaginal fluids, and iliac lymph nodes. After a single dose, plasma C(max) and AUC(0-4h) were significantly higher in the TFV 1% gel group compared with the reduced-glycerin TFV 1% gel group. After 14 days of once-daily dosing, differences in these parameters were insignificant. Vaginal fluid concentrations were ∼100 μg/ml following the first dose and up to a mean of about 500 μg/ml after 14 once-daily doses. Mean (and median) cranial TFV tissue concentrations were generally in excess of 100 μg/g following a single dose and 14 once-daily doses of both gels; concentrations in the caudal vaginal tissues were comparatively lower, although in nearly all cases mean values exceeded 10 μg/g. Treatment of tissues with phosphatase to liberate TFV from its diphosphate and monophosphate metabolites increased recovery of TFV by 60-120%. Median TFV concentrations in iliac lymph nodes ranged from 44 ng/g to 196 ng/g; differences between iliac lymph node TFV concentrations following dosing of the two gels were insignificant. There were no differences observed in histological evaluation in the cranial vagina following 14 days of once-daily dosing of either gel. There was an apparent impact of TFV on rabbit vaginal epithelium (increased secretory depletion and increased cellular vacuolization) independent of formulation. These data indicate that the reduced-glycerin TFV 1% gel may be a suitable alternative to TFV 1% gel.