Background:  Studies on HIV pre-exposure prophylaxis (PrEP) in women have shown mixed results, 2 large studies of oral PrEP being halted early. Even successful studies of oral PrEP has shown efficacy to be dependent on adherence to dosing. Rilpivirine Long-Acting (RPV-LA) is a parenteral formulation containing 300 mg/mL, allowing prolonged plasma exposure and potentially monthly or less frequent dosing. This study explores the pharmacokinetics in plasma, the female genital tract and male rectum over 84 days after a single intramuscular dose.

Methods:  This prospective, open-label stratified-dose exploratory study investigated plasma and body fluid/tissue pharmacokinetics in healthy volunteers with low behavioral risk for HIV. Volunteers aged 18 to 50 were screened for general health, HIV and sexually transmitted infections. Female participants received a single intramuscular dose (gluteus maximus) at 300, 600, or 1200 mg with plasma for RPV levels collected on days 0 (pre-dose and 4 and 8 hours), 1, 3, 7, 11, 14, 21, 28, 42, 56, and 84 hours and genital tract fluid at a similar times from 8 hours onward. Biopsies of vaginal epithelium from the peri-cervical fornices were taken at days 14 and (7 or 28) for tissue pharmacokinetics. A small sub-study of males received an intramuscular dose of 600 mg, with plasma pharmacokinetics (a similar schedule) and rectal biopsies at days 7 and 14. RPV concentrations were determined by a validated HPLC-MS/MS method (calibration range 0.2 to 200 ng/mL); pharmacokinetics parameters (AUC_84d and C_84d, C_max) were calculated using WinNonLin.

Results:  At the St. Stephen’s Center, London, we recruited 27 eligible female participants:  >50% being of self-identified as African or African Caribbean ethnicity; 6 male participants were recruited to the rectum sub-study. Plasma and genital tract fluid pharmacokinetics and vaginal and rectal tissue concentrations are presented in the table. All doses were well tolerated; no serious adverse event and no prolongation of QT interval on ECG.

Conclusions:  All 3 RPV-LA doses exhibit prolonged plasma and genital tract exposure supporting further exploration as potential PrEP agent. Partitioning between tissue compartments shows higher concentrations (at least equivalent or higher) in genital tract fluid, an important site of action. Vaginal tissue concentrations were slightly lower than genital tract fluid, possibly due to the non-secretory nature of this mucosa; more data needed to understand this phenomenon. Male rectum concentrations were equivalent to those in plasma. The safety, pharmacokinetics and pharmacodynamics after multiple IM RPV-LA doses will be important further information for future development.