Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women
| Autor: | Gustavo F. Doncel, Vivian Brache, Jill L. Schwartz, Raina N. Fichorova, Debra H. Weiner, Betsy C. Herold, Neelima Chandra, Andrea R. Thurman, Susana N. Asin, Mark A. Marzinke, Timothy J. McCormick, Charlene S. Dezzutti, Frank Z. Stanczyk, Sharon L. Hillier, Meredith R. Clark, Christiane Rollenhagen, Patrick F. Kiser |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
RNA viruses Physiology Biopsy Maternal Health lcsh:Medicine HIV Infections Pathology and Laboratory Medicine law.invention 0302 clinical medicine Endocrinology Randomized controlled trial Immunodeficiency Viruses law Animal Cells Reproductive Physiology Pregnancy Medicine and Health Sciences Levonorgestrel 030212 general & internal medicine lcsh:Science media_common Multidisciplinary Obstetrics and Gynecology Drugs Contraceptives Genomics Contraception Medical Microbiology Viral Pathogens Viruses Female Pathogens Cellular Types medicine.drug Research Article Biotechnology Adult medicine.medical_specialty endocrine system media_common.quotation_subject Urology Surgical and Invasive Medical Procedures Microbial Genomics Placebo Models Biological Microbiology 03 medical and health sciences Pharmacokinetics Retroviruses medicine Genetics Humans Female Contraception Adverse effect Tenofovir Ovulation Microbial Pathogens Menstrual cycle Menstrual Cycle Pharmacology Endocrine Physiology business.industry lcsh:R Lentivirus Organisms Contraceptive Devices Female Biology and Life Sciences HIV Cell Biology Sperm 030104 developmental biology Germ Cells Pharmacodynamics HIV-1 Women's Health lcsh:Q Medical Devices and Equipment Microbiome business |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 6, p e0199778 (2018) |
| ISSN: | 1932-6203 |
| Popis: | To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94-100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score |
| Databáze: | OpenAIRE |
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