delivery from matrix and reservoir intravaginal rings to HIV-negative women.

Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women.

Vaginal microbicides for the prevention of HIV transmission may be an important option for protecting women from infection. Incorporation of dapivirine, a lead candidate nonnucleoside reverse transcriptase inhibitor, into intravaginal rings (IVRs) for sustained mucosal deliverymay increase microbicide product adherence and efficacy compared with conventional vaginal formulations. Twenty-four healthy HIV-negative women 18-35 years of age were randomly assigned (1:1:1) to dapivirine matrix intravaginal ring, dapivirine reservoir intravaginal ring, or placebo intravaginal ring. Dapivirine concentrations were measured in plasma and vaginal fluid samples collected at sequential time points over the 33-day study period (28 days of intravaginal ring use, 5 days of follow-up). Safety was assessed by pelvic/colposcopic examinations, clinical laboratory tests, and adverse events. Both intravaginal ring types were safe and well tolerated with similar adverse events observed in the placebo and dapivirine groups. Dapivirine from both intravaginal ring types was successfully distributed throughout the lower genital tract at concentrations over 4 logs greater than the EC50 against wild-type HIV-1 (LAI) in MT4 cells. Maximum concentration (Cmax) and area under the concentration-time curve (AUC) values were significantly higher with the matrix than reservoir intravaginal ring. Mean plasma concentrations of dapivirine were <2>

The idea of an intravaginal ring carrying an antiretroviral for HIV prevention and needing replacement once a month or less is attractive. This study found that such rings, carrying the nonnucleoside reverse transcriptase inhibitor dapivirine, were safe, well-tolerated, and produced high levels of dapirivine in cervicovaginal secretions. The rings tested released drug through different mechanisms but pharmacokinetic studies found that systemic exposure of dapivirine in the blood was low with both of them. Now it’s on to the next stage!