1. Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model
- Author
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Mandelbrot, Laurent, Ceccaldi, Pierre-François, Duro, Dominique, Lê, Minh, Pencolé, Lucile, Peytavin, Gilles, Service de Gynécologie-Obstétrique [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Louis Mourier - AP-HP [Colombes], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), DHU Risques Et Grossesse, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC), Service de Gynécologie-Obstétrique [Clichy], Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Service de Pharmaco-Toxicologie [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], The salary of Dominique Duro was funded by the Agence Nationale de Recherches sur le Sida et Hépatites Virales (Inserm-ANRS). The Agence Nationale de Recherches sur le Sida et Hépatites Virales (Inserm-ANRS) also also provided funding to purchase equipment and for publication costs., Bodescot, Myriam, Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Beaujon [AP-HP]
- Subjects
RNA viruses ,Embryology ,Placenta ,Maternal Health ,Pathology and Laboratory Medicine ,Biochemistry ,Piperazines ,Immunodeficiency Viruses ,Drug Metabolism ,Pregnancy ,Medicine and Health Sciences ,Public and Occupational Health ,Maternal-Fetal Exchange ,Obstetrics and Gynecology ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Vaccination and Immunization ,[SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences ,Perfusion ,Medical Microbiology ,Viral Pathogens ,Viruses ,Medicine ,Female ,Anatomy ,Pathogens ,Heterocyclic Compounds, 3-Ring ,Research Article ,Pyridones ,Science ,Immunology ,Antiretroviral Therapy ,[SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,Microbiology ,Models, Biological ,Antiviral Therapy ,Albumins ,Retroviruses ,Oxazines ,Placental Cotyledon ,Humans ,Pharmacokinetics ,HIV Integrase Inhibitors ,Microbial Pathogens ,Pharmacology ,Lentivirus ,Reproductive System ,Organisms ,Biology and Life Sciences ,Proteins ,HIV ,[SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,Women's Health ,Preventive Medicine ,Antipyrine ,Developmental Biology - Abstract
ObjectiveTo determine the transplacental pharmacokinetics of the HIV integrase inhibitor dolutegravir.Study designMaternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in 5 closed-circuit, recirculating experiments. Dolutegravir was added to a maternal perfusate containing antipyrine, a marker to validate the cotyledon's viability, and 2 g/liter of human albumin.ResultsAfter 3h of recirculating perfusion, the mean (± SD) DTG concentrations in the maternal and in the fetal compartments were respectively 2450 ± 286 ng/mL and 715 ± 369 ng/mL, with a fetal-to-maternal ratio of 34% ± 18% and a clearance index (in comparison with antipyrine transfer) of 79% ± 23%. The mean cotyledon accumulation index was 153% ± 25%.ConclusionFetal transplacental exposure to dolutegravir was considerable as well as accumulation in placental tissue. Whether this may lead to risks for the exposed fetus requires more investigation.
- Published
- 2019