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Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: a Double-Blind Randomized Trial.
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JAIDS Journal of Acquired Immune Deficiency Syndromes: May 28 2015 Chen, Beatrice A. MD MPH; Panther, Lori MD MPH; Marzinke, Mark A. PhD; Hendrix, Craig W. MD; Hoesley, Craig J. MD; van der Straten, Ariane PhD MPH; Husnik, Marla J. MS; Soto-Torres, Lydia MD MPH; Nel, Annalene MD PhD; Johnson, Sherri MPH; Richardson-Harman, Nicola PhD; Rabe, Lorna K. BS; Dezzutti, Charlene S. PhD
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 multi-site, double-blind, randomized, placebo-controlled trial in 48 HIV-negative U.S. women, evaluated vaginal rings containing dapivirine (25 mg) and maraviroc (100 mg), dapivirine-only, maraviroc-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 to placebo. Dapivirine and maraviroc concentrations rose higher initially before falling more rapidly with the combination ring compared to relatively stable concentrations with the single drug rings. Dapivirine concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. Maraviroc was consistently detected only in CVF. Dapivirine and maraviroc CVF and dapivirine tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and dapivirine levels.
Conclusions: In this first study of a combination microbicide vaginal ring, all four rings were safe and well tolerated. Tissue dapivirine concentrations were 1,000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. Dapivirine, but not maraviroc, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Since maraviroc concentrations were consistently detectable only in CVF and not in plasma, improved drug release of maraviroc rings is needed.
Compared to the early DPV plateau with the DPV ring, the early peak and gradual fall in concentration in the DPV/MVC ring and MVC ring indicates an inefficient drug delivery profile that results in excess drug exposure early (risking toxicity) and lower concentrations later (risking lack of efficacy).
In addition, MVC is a substrate of p-glycoprotein and has been shown to have much greater permeability in cell cultures in the basolateral to apical direction than in the opposite direction.34 Since p-glycoprotein is present in the female lower genital tract, there may be active transport of maraviroc out of tissue.35 This may at least partially explain why MVC was below LLOQ in all cervical tissue biopsies in DPV/MVC ring users, in which case the combination ring will need to be reformulated to release higher levels of MVC to overcome the efflux out of the tissue. Further research is needed to investigate the feasibility of maraviroc as a vaginal microbicide.
In summary, DPV, but not MVC, delivered by a vaginal ring for 28 days provided dose dependent inhibition of HIV infection ex vivo in cervical tissue. Vaginal rings were safe and well-tolerated across all treatment arms. These data suggest that delivery of NNRTIs via vaginal rings is a promising approach for HIV prevention. More work is needed to determine the appropriate scaling of ex vivo and clinical concentration targets (IC90), and to improve the release characteristics of ARVs from the combination and MVC ring.

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