Abstract
Dapivirine (DPV) is a potent NNRTI used to prevent the sexual transmission of HIV. In a phase 1 trial (IPM 028), the concomitant use of a DPV vaginal ring and an antifungal miconazole (MIC) vaginal capsule was found to increase the systemic exposure to DPV in women, suggesting a potential for drug-drug interactions. This study’s objective was to investigate the mechanism of DPV-MIC interactions using drug-metabolizing enzymes (DMEs; CYPs and UGTs) that are locally expressed in the female reproductive tract (FRT). In vitro studies were performed to evaluate the metabolism of DPV and its inhibition and induction potential with DMEs. In addition, the impact of MIC on DPV metabolism and the inhibitory potential of DPV with DMEs were studied. Our findings suggest that DPV is a substrate of CYP1A1 and CYP3A4 enzymes and that MIC significantly decreased the DPV metabolism by inhibiting these two enzymes. DPV demonstrated potent inhibition of CYP1A1 and moderate/weak inhibition of the six CYP and eight UGT enzymes evaluated. MIC showed potent/moderate inhibition of seven CYP enzymes and weak/no inhibition of eight UGT enzymes. The combination of DPV and MIC showed potent inhibition of seven CYP enzymes (1A1, 1A2, 1B1, 2B6, 2C8, 2C19, and 3A4) and four UGT enzymes (1A3, 1A6, 1A9, and 2B7). DPV was not an inducer of CYP1A2, CYP2B6, and CYP3A4 enzymes in primary human hepatocytes. Therefore, the increased systemic concentrations of DPV observed in IPM 028 were likely due to the reduced metabolism of DPV because of CYP1A1 and CYP3A4 enzymes inhibition by MIC in the FRT.
Highlights
Introduction published maps and institutional affilSexual transmission of the human immunodeficiency virus (HIV) is a major threat to women’s health worldwide
The panel of enzymes selected for this work was based upon the enzyme expression in the human female reproductive tract (FRT) [17,18,19] and on the recommendations of regulatory guidelines [21,22]
The current study evaluates the potential for drug-drug interactions (DDI) to occur through interactions with drug-metabolizing enzymes (DMEs) involved in metabolism, inhibition, and induction when DPV is co-administered with other vaginal products
Summary
Sexual transmission of the human immunodeficiency virus (HIV) is a major threat to women’s health worldwide. Around 5000 young women ages 15–24 years acquire HIV [1]. There are only two licensed oral pre-exposure prophylaxis (PrEP) products, and only Truvada is approved for cisgender women who engage in receptive vaginal sex, whilst Descovy is approved for transgender women who have sex with men [2,3]. Uptake of oral PrEP has been below global targets for a number of reasons, including the challenges of taking a pill every day as is necessary to achieve high efficacy in cisgender women. It is important to develop additional options, such as topical PrEP, to meet the diverse needs of women across their reproductive life span.
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