Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women

Nel, Annaléne; Coplan, Paul; Wijgert, Janneke van de; Kapiga, Saidi; Mollendorf, Claire von; Geubbels, Eveline; Vyankandondera, Joseph; Rees, Helen; Masenga, Gileard; Kiwelu, Ireen; Moyes, J.; Smythe, Shanique C

doi:10.1097/qad.0b013e32832c413d

Cited by 78 publications

(66 citation statements)

References 15 publications

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“…All the plasma samples that were obtained in the dapivirine group were analyzed for dapivirine with the use of high-performance liquid chromatography-tandem mass spectrometry. 7 Residual levels of dapivirine were determined in all used active rings and in a subgroup of placebo rings with the use of high-performance liquid chromatography-ultraviolet testing. 8…”

Section: Analyses Of Plasma Samples and Returned Ringsmentioning

confidence: 99%

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: Analyses Of Plasma Samples and Returned Ringsmentioning

confidence: 99%

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

et al. 2016

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“…Phase III clinical trials of the dapivirine vaginal ring were initiated in early 2012. Pharmacokinetic data are available from multiple clinical studies with the dapivirine vaginal ring (14) and dapivirine gel formulations (15)(16)(17) and from studies in rhesus macaques and rabbits using radiolabeled dapivirine in a gel formulation (18).…”

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The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

Holt

Cameron²,

Dias³

et al. 2015

Antimicrob Agents Chemother

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dWhen developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. With an estimated 2.3 million new human immunodeficiency virus type 1 (HIV-1) infections in 2012 (1) and a total number of people living with HIV estimated at 35.3 million in the same year, the need for effective prevention strategies remains critical. Although barrier prevention strategies, such as male and female condoms, are effective, and behavioral programs teaching the benefits of monogamy and abstinence have shown some success (2-4), they have not significantly impacted the epidemic. One area of key concern is sub-Saharan Africa, where 57% of HIV-infected people are women (1). In order to provide prevention strategies to women in this high-risk population, locally (vaginally or rectally) applied products containing potent antiretroviral drugs are being developed by many different groups. These microbicides represent one of the most promising prophylactic strategies currently being developed in terms of being simple to self-administer, relatively easy to produce, and by virtue of the lower drug levels required compared to those with systemic approaches, the potential to be within reach of the health system and nongovernmental organization (NGO) budgets in the developing world. A key advantage to the topical microbicide approach is also that the same targeted active ingredient...

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“…[1][2][3][4] A number of excipients with diverse functions are frequently used in vaginally administered drug products, including the vaginal microbicides tested in preclinical and clinical studies for topical preexposure prophylaxis (PrEP) of sexually transmitted HIV-1. [5][6][7][8] In the design and development of vaginal formulations, the effect of formulation ingredients on the integrity of the cervicovaginal epithelium should be carefully evaluated. This is especially true in the formulation of vaginal microbicides, which are intended for the prevention of sexually transmitted infections (STIs).…”

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confidence: 99%

The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue

Zhou

Dezzutti

et al. 2016

AIDS Research and Human Retroviruses

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Pharmaceutical excipients are widely used in vaginal drug products. The epithelial integrity of the cervicovaginal tissue is important for HIV-1 prevention. However, the effects of excipients on cervicovaginal epithelium remain unknown. This study aims at assessing the effects of vaginal product excipients on the integrity of human cervicovaginal epithelium and on a lead HIV prevention antiretroviral drug, tenofovir (TFV). In the current study, nine excipients commonly used in vaginal formulations were incubated for 6 h with excised human ectocervical tissue. The effects of the excipients were examined by measuring the transepithelial electrical resistance (TEER), epithelial morphology, paracellular/transcellular permeability, and cell viability. The efficacy of TFV for preventing HIV-1 infection in the ex vivo cultured ectocervix was also tested. We found that disodium ethyl-enediaminetetraacetate (EDTA), sorbic acid, and benzoic acid had no effect on the tissue TEER. Butylated hydroxyanisole, glycerin, propylene glycol, methylparaben, and propylparaben slightly to moderately decreased tissue TEER, whereas citric acid significantly decreased the TEER in a time-dependent manner. Tissue morphology observed post-exposure strongly correlated with TEER data; however, a less strong correlation was observed between paracellular permeability and TEER data after exposure to different excipients. In addition, treatment with EDTA, methylparaben, and propylene glycol at tested levels had no effect on the efficacy of TFV in preventing tissue HIV-1 infection. In conclusion, the combined measurements of TEER, morphology, permeability, and viability using human cervicovaginal tissue represent a clinically relevant platform for safety evaluation of excipients and formulated products for HIV-1 prevention.

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Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women

Abstract: Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

Cited by 78 publications

References 15 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

The Sheep as a Model of Preclinical Safety and Pharmacokinetic Evaluations of Candidate Microbicides

The Effect of Commonly Used Excipients on the Epithelial Integrity of Human Cervicovaginal Tissue

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