Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women

Chen, Beatrice A.; Zhang, Jingyang; Gundacker, Holly; Hendrix, Craig W.; Hoesley, Craig; Salata, Robert A.; Dezzutti, Charlene S.; Straten, Ariane van der; Hall, Wayne; Jacobson, Cindy; Johnson, Sherri; McGowan, Ian; Nel, Annaléne; Soto-Torres, Lydia; Marzinke, Mark A.

doi:10.1093/cid/ciy654

Cited by 23 publications

(16 citation statements)

References 26 publications

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“…DPV was quantified in plasma and cervical tissue using previously described, liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) by the Clinical Pharmacology Analytical Laboratory at the Johns Hopkins University School of Medicine [24,25]. A modified version of a previously published LC‐MS method, which employed CVF extraction from Dacron swabs via a 1:1 solution of methanol:water, was used for DPV quantitation in CVF [26].…”

Section: Methodsmentioning

confidence: 99%

Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States

et al. 2021

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Introduction Vaginal rings are a promising approach to provide a woman‐centred, long‐acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV‐1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three‐month rings with different DPV dosages, compared with the monthly DPV ring. Methods From December 2017 to October 2018, MTN‐036/IPM‐047 enrolled 49 HIV‐negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three‐month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow‐up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginal fluid (CVF) and cervical tissue, at nominal timepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. Results There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs in the extended duration versus monthly ring arms ( p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervical tissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at all times, with no product discontinuations/outages) with no differences between the monthly versus three‐month rings. Most participants found the ring acceptable (median = 8 on 10‐point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms ( p = 0.01 and p = 0.15 respectively). Conclusions The extended duration DPV rings were well‐tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three‐month DPV rings for HIV prevention.

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Section: Methodsmentioning

confidence: 99%

Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States

et al. 2021

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“…The differences correlated with reduced adherence in younger women. Safety assessment, PK and acceptability of the DPV vaginal ring [37] confirmed its therapeutic potential. DPV plasma levels were also comparable in all enrolled women.…”

Section: Implantablesmentioning

confidence: 78%

“…Vaginal rings, well known for their use as birth control devices, are also being evaluated for extended ARV release [33][34][35][36][37][38]. Drugs used in rings are stabilized in either polymeric matrices or cores [33,34,36,39].…”

Section: Implantablesmentioning

confidence: 99%

The Promise of Long-Acting Antiretroviral Therapies: From Need to Manufacture

Gendelman

McMillan

Bade

et al. 2019

Trends in Microbiology

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Antiretroviral therapy has transformed human immunodeficiency virus infections from certain death to a manageable chronic disease. Achieving strict adherence to drug regimens that limit toxicities and viral resistance are achievable goals. Success is defined by halting viral transmission and by continuous viral restriction. A step towards improving treatment outcomes is in long acting antiretrovirals. While early results remain encouraging there remain opportunities for improvement. These rest, in part, on the required large drug dosing volumes, local injection site reactions and frequency of injections. Thus, implantable devices and long acting parenteral prodrugs have emerged which may provide more effective clinical outcomes. The recent successes in transforming native antiretrovirals into lipophilic and hydrophobic prodrugs stabilized into biocompatible surfactants can positively affect both. Formulating antiretroviral prodrugs demonstrate improvements in cell and tissue targeting, in drug dosing intervals and in the administered volumes of nanosuspensions. As such the newer formulations also hold the potential to suppress viral loads beyond more conventional therapies with the ultimate goal of HIV-1 elimination when combined with other modalities. KeywordsLong acting slow effective release antiretroviral therapy; regimen adherence; human immunodeficiency virus type one; viral reservoirs; good manufacturing practices; implantable devices Current Long Acting (LA) Antiretroviral Drug (ARV) FormulationsOral administration of antiretroviral (ARV) drugs is the major delivery route for treatment and prevention of human immunodeficiency virus type one (HIV-1) infection.

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“…Many of the advances in ring design and technology during the last twenty years have been driven by concerted global efforts to develop new antiretroviral-releasing ring products for preventing sexual transmission of HIV infection in women ( Vincent et al, 2018 ; Keller et al, 2019 ; Baum et al, 2015 ; Kiser et al, 2012 ; Woolfson et al, 2006 ; Malcolm et al, 2005 ; Baeten et al, 2020 ; Malcolm et al, 2016 ; Malcolm et al, 2014 ; van der Straten et al, 2016 ; Malcolm et al, 2010 ; Spence et al, 2015 ; Malcolm et al, 2012 ; Thurman et al, 2013 ). A matrix-type silicone elastomer vaginal ring providing sustained release of the antiretroviral drug dapivirine (DPV) – a potent non-nucleoside reverse transcriptase inhibitor – was developed by the International Partnership for Microbicides (IPM) to offer women a self-initiated, long-acting HIV prevention option ( Devlin et al, 2013 ; Nel et al, 2009 ; Nel et al, 2016a ; Baeten et al, 2016 ; McCoy et al, 2017 ; Nel et al, 2014 ; Chen et al, 2019 ; Bunge et al, 2020 ). In two Phase III safety and efficacy trials, the 25 mg DPV ring was shown to reduce the risk of HIV acquisition in women compared to a placebo ring ( Nel et al, 2016a ; Baeten et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Use of simulated vaginal and menstrual fluids to model in vivo discolouration of silicone elastomer vaginal rings

McCoy

Spence

Bashi

et al. 2021

International Journal of Pharmaceutics: X

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Vaginal rings releasing antiretrovirals – either alone or in combination with contraceptive progestins – are being developed for prevention of human immunodeficiency virus (HIV) transmission via vaginal sex. Following Phase I trials, significant discolouration was observed on the surface of investigational silicone elastomer antiretroviral-contraceptive matrix-type vaginal rings containing either 25 mg dapivirine or 200 mg dapivirine plus levonorgestrel. In this study, potential causes of the discolouration have been assessed in vitro using simulated vaginal and menstrual fluids (SVF and SMF, respectively) to model in vivo exposure. The fluid compositions also included hydrogen peroxide (H 2 O 2 ), hydrogen peroxide plus a copper intrauterine device (IUD), or synthetic dyes (representing personal care and household cleaning products). No discolouration was observed for rings exposed to SVF + hydrogen peroxide (with or without an IUD). However, the SVF + dye compositions showed significant ring discolouration, with staining patterns similar to those observed with rings that had been exposed to highly-coloured personal care and household cleaning products during clinical trial use. Exposure of rings to SMF compositions invariably caused yellow surface discolouration, dark spotting and markings, similar to the staining patterns observed following clinical use. The darker marks on the ring surface were identified as blood debris derived from the SMF. The study indicates that surface discolouration of rings in vivo can be attributed to exposure to menstrual fluid or highly coloured personal care or household cleaning products. Discolouration of the rings was not associated with any specific safety risks for the user, though severe discolouration could potentially impact acceptability and adherence.

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Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women

Cited by 23 publications

References 26 publications

Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States

Phase 1 pharmacokinetics and safety study of extended duration dapivirine vaginal rings in the United States

The Promise of Long-Acting Antiretroviral Therapies: From Need to Manufacture

Use of simulated vaginal and menstrual fluids to model in vivo discolouration of silicone elastomer vaginal rings

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