Effects of gel volume on pharmacokinetics for vaginal and rectal applications of combination DuoGel-IQB4012, a dual chamber-dual drug HIV microbicide gel, in pigtailed macaques.

Abstract

This study evaluated effects of differing gel volumes on pharmacokinetics (PK). IQB4012, a gel containing the non-nucleoside reverse transcriptase inhibitor IQP-0528 and tenofovir (TFV), was applied to the pigtailed macaque vagina and rectum. Vaginal gel volumes (1% loading of both drugs) were 0.5 or 1.5ml; following wash-out, 1 or 4ml of gel were then applied rectally. Blood, vaginal, and rectal fluids were collected at 0, 2, 4, and 24h. Vaginal and rectal tissue biopsies were collected at 4 and 24h. There were no statistically significant differences in concentrations for either drug between gel volumes within compartments at matched time points. After vaginal gel application, median IQP-0528 concentrations were ~ 104-105ng/g, 105-106ng/ml, and 103-105ng/ml in vaginal tissues, vaginal fluids, and rectal fluids, respectively (over 24h). Median vaginal TFV concentrations were 1-2 logs lower than IQP-0528 levels at matched time points. After rectal gel application, median IQP-0528 and TFV concentrations in rectal fluids were ~ 103-105ng/ml and ~ 102-103ng/ml, respectively. Concentrations of both drugs sampled in rectal tissues were low (~ 101-103ng/g). For 1ml gel, half of sampled rectal tissues had undetectable concentrations of either drug, and over half of sampled rectal fluids had undetectable TFV concentrations. These results indicate differences in drug delivery between the vaginal and rectal compartments, and that smaller vaginal gel volumes may not significantly compromise microbicide PK and prophylactic potential. However, effects of rectal gel volume on PK for both drugs were less definitive.