PMID- 30265679 OWN - NLM STAT- MEDLINE DCOM- 20190409 LR - 20190409 IS - 1549-1676 (Electronic) IS - 1549-1277 (Print) IS - 1549-1277 (Linking) VI - 15 IP - 9 DP - 2018 Sep TI - Safety and pharmacokinetics of single, dual, and triple antiretroviral drug formulations delivered by pod-intravaginal rings designed for HIV-1 prevention: A Phase I trial. PG - e1002655 LID - 10.1371/journal.pmed.1002655 [doi] LID - e1002655 AB - BACKGROUND: Intravaginal rings (IVRs) for HIV pre-exposure prophylaxis (PrEP) theoretically overcome some adherence concerns associated with frequent dosing that can occur with oral or vaginal film/gel regimens. An innovative pod-IVR, composed of an elastomer scaffold that can hold up to 10 polymer-coated drug cores (or "pods"), is distinct from other IVR designs as drug release from each pod can be controlled independently. A pod-IVR has been developed for the delivery of tenofovir (TFV) disoproxil fumarate (TDF) in combination with emtricitabine (FTC), as daily oral TDF-FTC is the only Food and Drug Administration (FDA)-approved regimen for HIV PrEP. A triple combination IVR building on this platform and delivering TDF-FTC along with the antiretroviral (ARV) agent maraviroc (MVC) also is under development. METHODOLOGY AND FINDINGS: This pilot Phase I trial conducted between June 23, 2015, and July 15, 2016, evaluated the safety, pharmacokinetics (PKs), and acceptability of pod-IVRs delivering 3 different ARV regimens: 1) TDF only, 2) TDF-FTC, and 3) TDF-FTC-MVC over 7 d. The crossover, open-label portion of the trial (N = 6) consisted of 7 d of continuous TDF pod-IVR use, a wash-out phase, and 7 d of continuous TDF-FTC pod-IVR use. After a 3-mo pause to evaluate safety and PK of the TDF and TDF-FTC pod-IVRs, TDF-FTC-MVC pod-IVRs (N = 6) were evaluated over 7 d of continuous use. Safety was assessed by adverse events (AEs), colposcopy, and culture-independent analysis of the vaginal microbiome (VMB). Drug and drug metabolite concentrations in plasma, cervicovaginal fluids (CVFs), cervicovaginal lavages (CVLs), and vaginal tissue (VT) biopsies were determined via liquid chromatographic-tandem mass spectrometry (LC-MS/MS). Perceptibility and acceptability were assessed by surveys and interviews. Median participant age was as follows: TDF/TDF-FTC group, 26 y (range 24-35 y), 2 White, 2 Hispanic, and 2 African American; TDF-FTC-MVC group, 24.5 y (range 21-41 y), 3 White, 1 Hispanic, and 2 African American. Reported acceptability was high for all 3 products, and pod-IVR use was confirmed by residual drug levels in used IVRs. There were no serious adverse events (SAEs) during the study. There were 26 AEs reported during TDF/TDF-FTC IVR use (itching, discharge, discomfort), with no differences between TDF alone or in combination with FTC observed. In the TDF-FTC-MVC IVR group, there were 12 AEs (itching, discharge, discomfort) during IVR use regardless of attribution to study product. No epithelial disruption/thinning was seen by colposcopy, and no systematic VMB shifts were observed. Median (IQR) tenofovir diphosphate (TFV-DP) tissue concentrations of 303 (277-938) fmol/10(6) cells (TDF), 289 (110-603) fmol/10(6) cells (TDF-FTC), and 302 (177.1-823.8) fmol/10(6) cells (TDF-FTC-MVC) were sustained for 7 d, exceeding theoretical target concentrations for vaginal HIV prevention. The study's main limitations include the small sample size, short duration (7 d versus 28 d), and the lack of FTC triphosphate measurements in VT biopsies. CONCLUSIONS: An innovative pod-IVR delivery device with 3 different formulations delivering different regimens of ARV drugs vaginally appeared to be safe and acceptable and provided drug concentrations in CVFs and tissues exceeding concentrations achieved by highly protective oral dosing, suggesting that efficacy for vaginal HIV PrEP is achievable. These results show that an alternate, more adherence-independent, longer-acting prevention device based on the only FDA-approved PrEP combination regimen can be advanced to safety and efficacy testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT02431273. FAU - Vincent, Kathleen L AU - Vincent KL AUID- ORCID: 0000-0003-3051-9551 AD - Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Moss, John A AU - Moss JA AUID- ORCID: 0000-0001-8091-3245 AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Marzinke, Mark A AU - Marzinke MA AUID- ORCID: 0000-0003-1670-8786 AD - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. AD - Department of Pathology, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Hendrix, Craig W AU - Hendrix CW AUID- ORCID: 0000-0002-5696-8665 AD - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America. FAU - Anton, Peter A AU - Anton PA AUID- ORCID: 0000-0002-4677-6782 AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. AD - Center for HIV Prevention Research, Division of Digestive Diseases and UCLA AIDS Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America. FAU - Pyles, Richard B AU - Pyles RB AUID- ORCID: 0000-0002-2215-5500 AD - Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America. AD - Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Guthrie, Kate M AU - Guthrie KM AUID- ORCID: 0000-0002-5528-1212 AD - The Centers for Behavioral & Preventive Medicine, The Miriam Hospital, Providence, Rhode Island, United States of America. AD - Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America. FAU - Dawson, Lauren AU - Dawson L AD - Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Olive, Trevelyn J AU - Olive TJ AD - Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, United States of America. FAU - Butkyavichene, Irina AU - Butkyavichene I AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Churchman, Scott A AU - Churchman SA AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Cortez, John M Jr AU - Cortez JM Jr AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Fanter, Rob AU - Fanter R AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Gunawardana, Manjula AU - Gunawardana M AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Miller, Christine S AU - Miller CS AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Yang, Flora AU - Yang F AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. FAU - Rosen, Rochelle K AU - Rosen RK AD - The Centers for Behavioral & Preventive Medicine, The Miriam Hospital, Providence, Rhode Island, United States of America. AD - Department of Behavioral & Social Sciences, Brown University School of Public Health, Providence, Rhode Island, United States of America. FAU - Vargas, Sara E AU - Vargas SE AUID- ORCID: 0000-0003-2934-4766 AD - The Centers for Behavioral & Preventive Medicine, The Miriam Hospital, Providence, Rhode Island, United States of America. AD - Department of Psychiatry & Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island, United States of America. FAU - Baum, Marc M AU - Baum MM AUID- ORCID: 0000-0003-1558-5649 AD - Department of Chemistry, Oak Crest Institute of Science, Monrovia, California, United States of America. LA - eng SI - ClinicalTrials.gov/NCT02431273 GR - R44 HD075636/HD/NICHD NIH HHS/United States GR - U19 AI113048/AI/NIAID NIH HHS/United States GR - UL1 TR001439/TR/NCATS NIH HHS/United States GR - UL1 TR001079/TR/NCATS NIH HHS/United States GR - P30 AI094189/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20180928 PL - United States TA - PLoS Med JT - PLoS medicine JID - 101231360 RN - 0 (Anti-HIV Agents) RN - 99YXE507IL (Tenofovir) RN - G70B4ETF4S (Emtricitabine) RN - MD6P741W8A (Maraviroc) SB - IM MH - Administration, Intravaginal MH - Adult MH - Anti-HIV Agents/*administration & dosage/adverse effects/pharmacokinetics MH - Contraceptive Devices, Female MH - Cross-Over Studies MH - Drug Compounding MH - Drug Delivery Systems MH - Emtricitabine/administration & dosage/adverse effects/pharmacokinetics MH - Female MH - HIV Infections/*prevention & control MH - *HIV-1 MH - Humans MH - Maraviroc/administration & dosage/adverse effects/pharmacokinetics MH - Patient Satisfaction MH - Pre-Exposure Prophylaxis/*methods MH - Tenofovir/administration & dosage/adverse effects/pharmacokinetics MH - Young Adult PMC - PMC6161852 COIS- I have read the journal's policy and the authors of this manuscript have the following competing interests: During part of the time of the study, IB, SAC, and JMC were employees of Auritec and participated in manufacturing the vaginal rings; they were no longer employees at the time of sample collection, data analysis, and manuscript preparation. Prior to August 2016, MG was a 50% shared employee of Auritec and participated in the residual drug measurements and coordinating sample distribution. JAM and MMB are co-inventors on patent applications that include aspects of the intravaginal ring device that was used in the clinical trial described in this manuscript and have received funding for preclinical research relevant to HIV (but not vaginal rings) from ViiV/GSK. They also have received funding from the International Partnership for Microbicides, CONRAD, and the Population Council. JAM, MMB, and MG are co-inventors on the following patent applications relevant to HIV: https://patents.google.com/patent/WO2016149561A1/en and https://patents.google.com/patent/WO2017161136A1/en. KLV and RBP are paid consultants to ABL, Inc. CWH has received funding for clinical research from ViiV/GSK managed via Johns Hopkins University and was a consultant for 1-2 days in 2017 to ViiV/GSK. EDAT- 2018/09/29 06:00 MHDA- 2019/04/10 06:00 PMCR- 2018/09/28 CRDT- 2018/09/29 06:00 PHST- 2017/06/19 00:00 [received] PHST- 2018/08/17 00:00 [accepted] PHST- 2018/09/29 06:00 [entrez] PHST- 2018/09/29 06:00 [pubmed] PHST- 2019/04/10 06:00 [medline] PHST- 2018/09/28 00:00 [pmc-release] AID - PMEDICINE-D-17-02138 [pii] AID - 10.1371/journal.pmed.1002655 [doi] PST - epublish SO - PLoS Med. 2018 Sep 28;15(9):e1002655. doi: 10.1371/journal.pmed.1002655. eCollection 2018 Sep.