A safety and pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women

Objectives:Women-initiated HIV-prevention products are urgently needed. To address this need, a trial was conducted to assess the safety and pharmacokinetics of a silicone elastomer matrix vaginal ring containing 25 mg of the antiretroviral drug dapivirine when used continuously for 28 consecutive days. Methods:A double-blind, randomized, placebo-controlled trial was conducted in 16 healthy, HIV-negative women, 18–40 years of age, who were randomized 1 : 1 to use either the active or matching placebo ring for 28 days. Participants were followed during and for 28 days after ring use for safety and pharmacokinetic evaluations. Results:The dapivirine vaginal ring was safe and well tolerated with no differences in safety endpoints between the active and placebo ring. The concentration–time plots of dapivirine in vaginal fluid were indicative of a sustained release of dapivirine over the 28 days of use. Dapivirine vaginal fluid concentrations were highest near the ring, followed by the cervix and introïtus (mean Cmax of 80, 67 and 31 &mgr;g/g, respectively). Vaginal fluid concentrations of dapivirine on the day of ring removal (day 28) at all three collection sites exceeded by more than 3900-fold the IC99 for dapivirine in a tissue explant infection model. Plasma dapivirine concentrations were low (<1 ng/ml) and remained well below those observed at the maximum tolerated dose for oral treatment (mean Cmax of 2286 ng/ml). Conclusion:The dapivirine vaginal ring has a safety and pharmacokinetic profile that supports its use as a sustained-release topical microbicide for HIV-1 prevention in women.