PMID- 30289485 OWN - NLM STAT- MEDLINE DCOM- 20200506 LR - 20200506 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 68 IP - 7 DP - 2019 Mar 19 TI - Phase 2a Safety, Pharmacokinetics, and Acceptability of Dapivirine Vaginal Rings in US Postmenopausal Women. PG - 1144-1151 LID - 10.1093/cid/ciy654 [doi] AB - BACKGROUND: Postmenopausal women have unique sociobiological human immunodeficiency virus (HIV) risks. We evaluated the safety, pharmacokinetics, and acceptability of a microbicide dapivirine (DPV) vaginal ring (VR) versus placebo in postmenopausal women. METHODS: We enrolled 96 HIV-negative postmenopausal US women in a phase 2a double-blind, randomized (3:1) trial of monthly VRs containing 25 mg DPV or placebo used continuously for 12 weeks. We assessed safety by adverse events (AEs). DPV concentrations were quantified in plasma and vaginal fluid. Steady-state concentrations were analyzed at 4, 8, and 12 weeks using repeated measures ANOVA. We assessed acceptability by self-report. RESULTS: We found no differences in the proportion of women with related grade 2 or higher reproductive system AEs (DPV: 6/72 (8%), placebo: 3/24 (13%), P = .68) or grade 3 or higher AEs (DPV: 4/72 (6%), placebo: 0/24 (0%), P = .57). In the DPV arm, 2/72 (3%) declined to resume product use due to AEs. Median DPV concentrations in plasma (262.0 pg/mL at week 12) and vaginal fluid (40.6 ng/mg at week 12) were constant over 12 weeks and exceeded the in vitro 50% effective concentration by 5000-fold in vaginal fluid by week 4. VR acceptability was high; 84/93 (90%) "very much liked or liked" the VR. CONCLUSIONS: DPV VRs were safe, well tolerated, and acceptable in postmenopausal women. Plasma concentrations were comparable to published data on DPV use in reproductive-age women (median plasma concentration: 264 pg/mL). Given the reassuring safety and pharmacokinetic data, the DPV VR is promising for preexposure prophylaxis in postmenopausal women. CLINICAL TRIALS REGISTRATION: NCT02010593. CI - (c) The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. FAU - Chen, Beatrice A AU - Chen BA AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh. AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania. FAU - Zhang, Jingyang AU - Zhang J AD - Statistical Center for HIV/AIDS Research and Prevention/Fred Hutchinson Cancer Research Center, Seattle, Washington. FAU - Gundacker, Holly M AU - Gundacker HM AD - Statistical Center for HIV/AIDS Research and Prevention/Fred Hutchinson Cancer Research Center, Seattle, Washington. FAU - Hendrix, Craig W AU - Hendrix CW AD - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. FAU - Hoesley, Craig J AU - Hoesley CJ AD - Department of Medicine, University of Alabama at Birmingham. FAU - Salata, Robert A AU - Salata RA AD - Department of Medicine, Case Western Reserve University, Cleveland, Ohio. FAU - Dezzutti, Charlene S AU - Dezzutti CS AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh. AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania. FAU - van der Straten, Ariane AU - van der Straten A AD - Women's Global Health Imperative (WGHI) RTI International, San Francisco, California. FAU - Hall, Wayne B AU - Hall WB AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania. FAU - Jacobson, Cindy E AU - Jacobson CE AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania. FAU - Johnson, Sherri AU - Johnson S AD - FHI 360, Durham, North Carolina. FAU - McGowan, Ian AU - McGowan I AD - Magee-Womens Research Institute, Pittsburgh, Pennsylvania. AD - Department of Medicine, University of Pittsburgh, Pennsylvania. FAU - Nel, Annalene M AU - Nel AM AD - International Partnership for Microbicides, Silver Spring. FAU - Soto-Torres, Lydia AU - Soto-Torres L AD - Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. FAU - Marzinke, Mark A AU - Marzinke MA AD - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. CN - MTN-024/IPM 031 Protocol Team for the Microbicide Trials Network LA - eng SI - ClinicalTrials.gov/NCT02010593 GR - UM1 AI069494/AI/NIAID NIH HHS/United States GR - UM1 AI068633/AI/NIAID NIH HHS/United States GR - UM1 AI068615/AI/NIAID NIH HHS/United States GR - UM1 AI106707/AI/NIAID NIH HHS/United States GR - UM1 AI069452/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - 0 (Anti-HIV Agents) RN - 0 (Placebos) RN - 0 (Pyrimidines) RN - TCN4MG2VXS (Dapivirine) SB - IM CIN - doi: 10.1093/cid/ciy652 CIN - doi: 10.1093/cid/ciy653 MH - Aged MH - Anti-HIV Agents/administration & dosage/*adverse effects/*pharmacokinetics MH - *Contraceptive Devices, Female MH - Double-Blind Method MH - Drug-Related Side Effects and Adverse Reactions/epidemiology MH - Female MH - Humans MH - Middle Aged MH - Patient Acceptance of Health Care/statistics & numerical data MH - Placebos/administration & dosage MH - Plasma/chemistry MH - *Postmenopause MH - Pyrimidines/administration & dosage/*adverse effects/*pharmacokinetics MH - United States PMC - PMC6424088 OTO - NOTNLM OT - dapivirine OT - menopause OT - microbicide OT - pre-exposure prophylaxis OT - vaginal rings EDAT- 2018/10/06 06:00 MHDA- 2020/05/07 06:00 PMCR- 2019/10/04 CRDT- 2018/10/06 06:00 PHST- 2018/04/13 00:00 [received] PHST- 2018/08/02 00:00 [accepted] PHST- 2018/10/06 06:00 [pubmed] PHST- 2020/05/07 06:00 [medline] PHST- 2018/10/06 06:00 [entrez] PHST- 2019/10/04 00:00 [pmc-release] AID - 5115671 [pii] AID - ciy654 [pii] AID - 10.1093/cid/ciy654 [doi] PST - ppublish SO - Clin Infect Dis. 2019 Mar 19;68(7):1144-1151. doi: 10.1093/cid/ciy654.