Post-use assay of vaginal rings (VRs) as a potential measure of clinical trial adherence

Spence, Patrick; Nel, Annaléne; Niekerk, Neliëtte van; Derrick, Tiffany; Wilder, Susan Z.; Devlin, Bríd

doi:10.1016/j.jpba.2016.03.023

Cited by 29 publications

(30 citation statements)

References 29 publications

(13 reference statements)

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“…However, the median residual level of dapivirine that was observed in the phase 1-2 trial and in two phase 1 trials 15,16 as well as in the Ring Study was 21 mg and is, therefore, probably a better indicator of sustained adherence to ring use. An exploratory time-varying productadherence analysis in which adherence was defined as a residual level of 21 mg or less of dapivirine in the ring showed a rate of HIV-1 acquisition that was 44% (95% CI, 7 to 67) lower during adherent periods than during nonadherent periods.…”

Section: Discussionmentioning

confidence: 93%

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women

et al. 2016

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BACKGROUNDThe incidence of human immunodeficiency virus (HIV) infection remains high among women in sub-Saharan Africa. We evaluated the safety and efficacy of extended use of a vaginal ring containing dapivirine for the prevention of HIV infection in 1959 healthy, sexually active women, 18 to 45 years of age, from seven communities in South Africa and Uganda. METHODSIn this randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned participants in a 2:1 ratio to receive vaginal rings containing either 25 mg of dapivirine or placebo. Participants inserted the rings themselves every 4 weeks for up to 24 months. The primary efficacy end point was the rate of HIV type 1 (HIV-1) seroconversion. RESULTSA total of 77 participants in the dapivirine group underwent HIV-1 seroconversion during 1888 person-years of follow-up (4.1 seroconversions per 100 person-years), as compared with 56 in the placebo group who underwent HIV-1 seroconversion during 917 person-years of follow-up (6.1 seroconversions per 100 person-years). The incidence of HIV-1 infection was 31% lower in the dapivirine group than in the placebo group (hazard ratio, 0.69; 95% confidence interval [CI], 0.49 to 0.99; P = 0.04). There was no significant difference in efficacy of the dapivirine ring among women older than 21 years of age (hazard ratio for infection, 0.63; 95% CI, 0.41 to 0.97) and those 21 years of age or younger (hazard ratio, 0.85; 95% CI, 0.45 to 1.60; P = 0.43 for treatment-by-age interaction). Among participants with HIV-1 infection, nonnucleoside reverse-transcriptase inhibitor resistance mutations were detected in 14 of 77 participants in the dapivirine group (18.2%) and in 9 of 56 (16.1%) in the placebo group. Serious adverse events occurred more often in the dapivirine group (in 38 participants [2.9%]) than in the placebo group (in 6 [0.9%]). However, no clear pattern was identified. CONCLUSIONSAmong women in sub-Saharan Africa, the dapivirine ring was not associated with any safety concerns and was associated with a rate of acquisition of HIV-1 infection that was lower than the rate with placebo. (Funded by the International Partnership for Microbicides; ClinicalTrials.gov number, NCT01539226.)

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Section: Discussionmentioning

confidence: 93%

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women

et al. 2016

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“…In general, dapivirine release is minimally affected by the inclusion of a non-medicated core, despite this resulting in a reduction in total dapivirine content in the ring (Table 1), as evidenced by comparing dapivirine release from rings B and C. Dapivirine loading in C is reduced by ~40% compared to ring B, and yet dapivirine release is similar, demonstrating that the ~4 mg, or 16%, of dapivirine that is released from a 25 mg torus matrix-type ring is due to drug located nearest the external surface of the device. (Spence et al, 2016) Therefore, blank cores may be a useful strategy for reducing drug loading, thereby reducing costs and wastage. Dapivirine release across the various ring designs is related to external surface area of the DPV loaded component of the ring.…”

Section: In Vitro Releasementioning

confidence: 99%

“…By comparison, in the 25 mg dapivirine-releasing vaginal ring, dapivirine is dispersed throughout the entire ring matrix. However, in clinical studies, only ~4 mg of the initial 25 mg dapivirine is released over 28 days, based on measurement of residual dapivirine in the ring following use (Spence et al, 2016). This ~4 mg quantity of dapivirine is released from those layers closest to the surface of ring for which the drug diffusion pathway is shortest, in accordance with well-established theory (Malcolm et al, 2003) and evidenced by the visual appearance of a drug depletion zone in the cross-sections of used matrix-type rings (Susan M .…”

Section: Pharmacokineticsmentioning

confidence: 99%

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

McBride

Malcolm

Dias

et al. 2019

International Journal of Pharmaceutics

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P. (2019). Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES. International Journal of Pharmaceutics, 564, 207-213. Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide Abstract The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginallyadministered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES isincorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women.

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“…HIV PrEP interventions currently in development include multipurpose vaginal rings containing ARVs to prevent sexual transmission of HIV in addition to hormonal contraceptives to prevent pregnancy [3]. New analytical approaches to assess adherence to multipurpose vaginal rings are needed to better evaluate the safety and efficacy of these new intervention strategies [2,4,5]. Residual levels of the ARV dapivirine in used vaginal rings have recently been used to inform measures of adherence and efficacy for vaginal rings in clinical trials for HIV prevention [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…New analytical approaches to assess adherence to multipurpose vaginal rings are needed to better evaluate the safety and efficacy of these new intervention strategies [2,4,5]. Residual levels of the ARV dapivirine in used vaginal rings have recently been used to inform measures of adherence and efficacy for vaginal rings in clinical trials for HIV prevention [5,6]. Our study sought to determine if residual synthetic hormone levels in used contraceptive vaginal rings could provide an objective measure of vaginal ring use during a clinical trial.…”

Section: Introductionmentioning

confidence: 99%

Residual hormone levels in used contraceptive rings as a measurement of adherence to vaginal ring use

et al. 2017

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Objective This study sought to measure residual contraceptive hormone levels in vaginal rings as an adherence marker for monitoring product use in clinical trials. Study design Residual etonogestrel and ethinyl estradiol levels from used NuvaRings® of 26 self-reported adherent women enrolled in a clinical trial of vaginal ring acceptability were compared to those from 16 women who used NuvaRing® as their contraceptive choice. Results Twenty-one (81%) clinical trial rings had contraceptive hormone levels within the range of those used as a contraceptive choice. Five returned rings had unused or discordant levels of residual contraceptive hormones. Conclusion Residual vaginal ring drug levels could help assess adherence in clinical trials.

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Post-use assay of vaginal rings (VRs) as a potential measure of clinical trial adherence

Cited by 29 publications

References 29 publications

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women

Safety and Efficacy of a Dapivirine Vaginal Ring for HIV Prevention in Women

Development and pharmacokinetics of a combination vaginal ring for sustained release of dapivirine and the protein microbicide 5P12-RANTES

Residual hormone levels in used contraceptive rings as a measurement of adherence to vaginal ring use

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