P18.06
Background: Pharmacokinetics (PK) of 5 microbicide formulations were assessed in the macaque model. Formulations reduced in size and dosage for macaque use were: 1 film and 1 gel delivering dapivirine (DPV, 0.5mg, 0.75mg respectively); 2 films and 1 gel delivering tenofovir (TFV, 3.4mg, 11.2mg, 15mg).
Methods: For each formulation, 8 macaques received one vaginal dose followed by blood and tissue samples for PK analysis. Plasma was collected prior to, and 1hr, 2hr, 4hr, 6hr, 8hr, 1day (d), 2d, and 7d post exposure. Cervical and vaginal biopsies were collected at 6hr, 1d, and 7d after DPV exposure; vaginal biopsies were collected 1d and 7d after TFV exposure.
Results: Plasma DPV levels peaked at median (IQR) 240 (76, 304) pg/ml after film compared to 123 (59, 215) pg/ml after gel administration. Dose-adjusted peak plasma levels trended toward being higher (p=0.065) with the film. Overall dose-adjusted drug exposure (area-under-the-curve [AUC]) was not different between DPV formulations. Higher vaginal tissue levels of DPV were measured after gel compared to film dosing (median 1223pg/sample vs 109pg/sample), at 6hr (p=0.029). DPV concentrations were higher in vaginal vs cervical tissues for both formulations at 6hr (p=0.023). All tissue levels were<1pg/sample 7d after drug exposure.
Plasma TFV levels peaked median 4hr after film vs 1hr after gel dosing; dose-adjusted values were not different for Cmax or AUC among all 3 formulations (NS). Dose-adjusted tissue concentrations of TFV and TFV-DP were generally higher with film compared to gel (p≤0.038) at 1d (highest) and 7d after dosing. All tissue levels were far below peak, but still detectable 7d after dosing in at least half of those receiving film and 3 of 8 receiving gel.
Conclusions: Gel delivered more DPV to tissues than film with similar plasma exposure. TFV plasma levels were reflective of the dose delivered, regardless of platform. Film formulations delivered more TFV and TFV-DP to tissues than gel.
