Safety and pharmacokinetic assessment of 28 day anti-HIV dapivirine intravaginal microbicide rings.
Background: Dapivirine (TMC 120) is a non-nucleoside reverse transcriptase inhibitor in development as a microbicide for prevention of HIV transmission. Formulation of dapivirine in intravaginal rings (IVRs) for 28 day use represents a potential means of increasing microbicide product adherence and efficacy. Methods: Dapivirine (25 mg) was incorporated into either matrix (drug dispersed evenly throughout) or in reservoir (drug localized to an inner core inside an unmedicated outer sheath) IVRs. Placebo rings were matrix type with no drug. A 24-participant, phase I, double-blind, randomized (1:1:1), placebo-controlled 28 day study was conducted in a single centre to evaluate delivery of dapivirine (plasma levels, vaginal fluids, pharmacokinetic parameters), and to assess local and systemic safety. Dapivirine levels were evaluated from plasma and vaginal fluid samples collected at sequential time points over a 24-hour period on Day 1 (post insertion) and Day 28 (post removal) and at sequential time points over a 33-day (28-day treatment; 5-day follow-up) period. Safety measurements were monitored over 33-day period. Results: Dapivirine concentrations were considerably higher for matrix than for reservoir rings during the entire 33 day period. Dapivirine concentrations were 73 times (plasma), 370 times (vaginal fluid, area of the ring), 610 times (vaginal fluid, at the cervix) and 195 times (vaginal fluid, area of the introitus) higher for matrix rings on day 1 of treatment. Differences in mean dapivirine concentrations between the two ring types decreased over the 28 days of use. Distribution throughout the genital tract was comparable with both rings. Systemic exposure to dapivirine was low, not exceeding 2ng/ml. A rapid increase in plasma concentrations was seen immediately after matrix ring insertion with mean peak concentrations observed 24 hours post ring insertion. None of the AEs reported were considered to be definitely or probably related to study treatment. Findings considered to be possibly related to intravaginal ring treatment were not different for the three treatment groups. No clinically relevant changes occurred compared to baseline. No serious or drug-related treatment-emergent AEs were reported. Conclusions: Different dapivirine IVR types were safe and well tolerated in healthy HIV-negative women. Pharmacokinetic data supports future development of dapivirine intravaginal rings as a monthly administered microbicide.
IPM clinical trial IPM018. CROI 2008. 15th conference on retroviruses and opportunistic infections, Boston, Massachusetts, USA, 3-6 February 2008, 559b.