PMID- 30101439 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20230928 IS - 1758-2652 (Electronic) IS - 1758-2652 (Linking) VI - 21 IP - 8 DP - 2018 Aug TI - FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir. PG - e25156 LID - 10.1002/jia2.25156 [doi] LID - e25156 AB - INTRODUCTION: Fast-dissolving vaginal film formulations release antiretroviral drugs directly into vaginal fluid and may be as efficient at drug delivery yet more acceptable to women than gels. In this Phase 1 vaginal film study, the safety, acceptability, pharmacokinetics and pharmacodynamics of two doses of tenofovir (TFV) film and TFV 1% gel were compared to corresponding placebo formulations. METHODS: Seventy-eight healthy HIV negative women were randomized to self-insert daily vaginal film (10 mg TFV, 40 mg TFV or placebo) or 4 mL of vaginal gel (TFV 1% [40 mg] or placebo) for seven days. Grade 2 and higher adverse events (AEs) related to study product were compared across study arms using Fisher's exact test. Plasma TFV concentrations were measured before and 2 hours after last product use. Paired cervical and vaginal tissue biopsies obtained 2 hours after the last dose were measured to determine tenofovir diphosphate (TFV-DP) concentrations and exposed to HIV in an ex vivo challenge assay. Acceptability was assessed through questionnaire. RESULTS: There was only one grade 2 or higher related AE, the primary endpoint; it occurred in the placebo gel arm. AEs occurred in 90% of participants; the majority (91%) were grade 1. AEs were similar across study arms. TFV concentrations in plasma and TFV-DP concentrations in cervical and vaginal tissues were comparable between 40 mg TFV film and the TFV gel groups. There was a significant relationship between reduced viral replication and TFV-DP concentrations in cervical tissues. Film users were less likely to report product leakage than gel users (66% vs. 100%, p < 0.001). CONCLUSIONS: Films were safe and well tolerated. Furthermore, films delivered TFV to mucosal tissues at concentrations similar to gel and were sufficient to block HIV infection of genital tissue ex vivo. CI - (c) 2018 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society. FAU - Bunge, Katherine E AU - Bunge KE AUID- ORCID: 0000-0003-3940-8102 AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Dezzutti, Charlene S AU - Dezzutti CS AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA. AD - Magee-Womens Research Institute, Pittsburgh, PA, USA. FAU - Hendrix, Craig W AU - Hendrix CW AD - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Marzinke, Mark A AU - Marzinke MA AD - Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Spiegel, Hans M L AU - Spiegel HML AD - Department of Health and Human Services, Kelly Government Solutions, Contractor to National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. FAU - Moncla, Bernard J AU - Moncla BJ AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA. AD - Magee-Womens Research Institute, Pittsburgh, PA, USA. FAU - Schwartz, Jill L AU - Schwartz JL AD - CONRAD, Eastern Virginia Medical School, Arlington, VA, USA. FAU - Meyn, Leslie A AU - Meyn LA AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Richardson-Harman, Nicola AU - Richardson-Harman N AD - Alpha StatConsult, Damascus MD, USA. FAU - Rohan, Lisa C AU - Rohan LC AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA. AD - Magee-Womens Research Institute, Pittsburgh, PA, USA. AD - Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA. FAU - Hillier, Sharon L AU - Hillier SL AD - Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA. AD - Magee-Womens Research Institute, Pittsburgh, PA, USA. LA - eng SI - ClinicalTrials.gov/NCT01989663 GR - HHSN272200800014C/AI/NIAID NIH HHS/United States GR - U19 AI082639/AI/NIAID NIH HHS/United States GR - UL1 TR000005/TR/NCATS NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PL - Switzerland TA - J Int AIDS Soc JT - Journal of the International AIDS Society JID - 101478566 RN - 0 (Anti-HIV Agents) RN - 0 (Vaginal Creams, Foams, and Jellies) RN - 99YXE507IL (Tenofovir) SB - IM MH - Adolescent MH - Adult MH - Anti-HIV Agents/administration & dosage/*pharmacokinetics MH - Chromatography, Liquid MH - Double-Blind Method MH - Female MH - HIV Infections/drug therapy/*prevention & control MH - Humans MH - Middle Aged MH - Pre-Exposure Prophylaxis MH - Tandem Mass Spectrometry MH - Tenofovir/administration & dosage/adverse effects/*pharmacokinetics MH - Vaginal Creams, Foams, and Jellies/administration & dosage/*therapeutic use MH - Virus Replication/drug effects MH - Young Adult PMC - PMC6088248 OTO - NOTNLM OT - microbicide OT - prevention OT - tenofovir OT - vaginal film OT - vaginal gel EDAT- 2018/08/14 06:00 MHDA- 2019/09/17 06:00 PMCR- 2018/08/13 CRDT- 2018/08/14 06:00 PHST- 2018/01/10 00:00 [received] PHST- 2018/06/01 00:00 [accepted] PHST- 2018/08/14 06:00 [entrez] PHST- 2018/08/14 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/08/13 00:00 [pmc-release] AID - JIA225156 [pii] AID - 10.1002/jia2.25156 [doi] PST - ppublish SO - J Int AIDS Soc. 2018 Aug;21(8):e25156. doi: 10.1002/jia2.25156.