Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial

Abstract

Background: Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery.

Methods: MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics.

Results: There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels.

Conclusions: In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.

Figure 1

Flowchart of participants * Participant withdrew after Day 29 visit; data prior to withdrawal were included in the analyses. DPV = dapivirine, MVC = maraviroc

Figure 2

Dapivirine and maraviroc cervicovaginal fluid concentrations over time. Concentrations below the limits of quantification are not shown. CVF, cervicovaginal fluid; DPV, dapivirine; MVC, maraviroc A. Cervicovaginal fluid dapivirine concentration vs. time plot (mean ± SD) B. Cervicovaginal fluid maraviroc concentration vs. time plot (mean ± SD)

Figure 2

Dapivirine and maraviroc cervicovaginal fluid concentrations over time. Concentrations below the limits of quantification are not shown. CVF, cervicovaginal fluid; DPV, dapivirine; MVC, maraviroc A. Cervicovaginal fluid dapivirine concentration vs. time plot (mean ± SD) B. Cervicovaginal fluid maraviroc concentration vs. time plot (mean ± SD)

Figure 3

Pharmacodynamic and pharmacokinetic correlations from fresh cervical tissue collected from women using DPV/MVC (open triangle), DPV only (black circle) and MVC only (grey square) vaginal rings. Ex vivo p24 and drug concentrations were measured from tissue samples taken on Day 28 following the active treatment. Supernatant p24 was collected on Days 4, 7, and 11 of the ex vivo HIV challenge assay. DPV (A-C, Days 4, 7, and 11) and MVC (D-F, Days 4, 7, and 11) cervical tissue concentrations (Log₁₀ ng/mL) are plotted against p24 log₁₀ pg/mL. The pharmacokinetic (MVC or DPV) and pharmacodynamic (p24) data were fit with an inverse, linear least squares regression at each day of the ex vivo assay with significance noted. Data below the limit of quantification were imputed as half the lower limit of quantification (DPV = −1.6 log₁₀ ng/mL; MVC = −1.0 log₁₀ ng/mL) and indicated with a vertical dotted line in the figures. DPV, dapivirine; MVC, maraviroc; LLOQ, lower limit of quantification; VR, vaginal ring