Revista de SIDA e investigación clínica

Pharmacokinetics and Safety Assessment of Anti-HIV Dapivirine Vaginal Microbicide Rings with Multiple Dosing

Abstract

Annalene M Nel, Wouter Haazen, Jeremy P Nuttall, Joseph W Romano, Pedro MM Mesquita, Betsy C Herold, Zeda F Rosenberg and Neliette van Niekerk

Objectives: Self-administered vaginal rings are a promising method for delivery of topical anti-HIV microbicides and might offer an adherence advantage over daily or coitally-dependent dosage forms such as gels. This trial assessed the safety and pharmacokinetic aspects of the Dapivirine Vaginal Ring-004 when worn as multiple rings over sequential periods of ring use by healthy, sexually-active, HIV-negative women. Methods: This double-blind trial was conducted among 48 women (18-40 years). Participants were randomly assigned to two groups (A or B) and received (3:1) either the dapivirine or a placebo vaginal ring. Group A used two rings over a 56-day period and Group B used three rings over a 57-day period. Safety evaluations were conducted throughout the trial. Dapivirine concentrations were measured in plasma, vaginal fluid and cervical tissue samples collected during and after the 56 days (Group A) or 57 days (Group B) of vaginal ring use. Results: Ring-004 was safe and well tolerated in all participants. The pharmacokinetic profile demonstrated a rapid increase in plasma and vaginal fluid concentrations and achieved concentrations in vaginal fluids and cervical tissue well above the in vitro IC99 in cervical tissue (3.3 ng/mL) that were sustained for a 28 to 35-day ring use period (approximately 3000 times higher in vaginal fluids and 14 -1000 times higher in cervical tissue). Drug levels were associated with significant inhibitory activity of genital secretions against HIV ex vivo, a biomarker of pharmacodynamics. Individual plasma dapivirine concentrations did not exceed 553 pg/mL and were well below plasma concentrations at the maximum tolerated dose for oral treatment (mean Cmax 2286 ng/mL). Conclusions: The consecutive use of several rings over a period of up to 57 days was safe and well tolerated, and PK data indicate that a single Ring-004 is likely to be protective for at least 35 days.