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Placental Transfer of the integrase strand inhibitors cabotegravir and bictegravir in the Ex Vivo Human Cotyledon Perfusion Model

Abstract : Data on placental transfer is lacking for the recent HIV integrase inhibitors, bictegravir and cabotegravir, although their future use in pregnancy is to be expected. The objective of this study was to determine their transplacental pharmacokinetics.Maternal-to-fetal transfer was investigated using the open-circuit ex-vivo dually perfused human cotyledon model.Cabotegravir or bictegravir was added to a maternal perfusate containing 2 g/l of human albumin and antipyrine, a marker to validate the cotyledon's viability, and cotyledons were dually perfused for up to 90 min.For cabotegravir, in five experiments, the median (IQR 25-75) cabotegravir concentrations in the maternal and in the fetal compartments were, respectively, 550 ng/ml (344-788) and 48 ng/ml (37-54), with a maternal-to-fetal ratio of 10% (5-16) and a clearance index (in comparison with antipyrine transfer) of 22% (19-28). The median cotyledon accumulation index was 10% (2-21).For bictegravir, in six experiments, the median (IQR 25-75) bictegravir concentrations in the maternal and in the fetal compartments were, respectively, 1650 ng/ml (1455-1960) and 126 ng/ml (112-142), with a maternal-to-fetal ratio of 7% (6-9.5) and a clearance index (in comparison with antipyrine transfer) of 21% (17-29). The median cotyledon accumulation index was 4% (3-5).Placental transfer of cabotegravir and bictegravir were low. This may not only limit the potential for fetal toxicities but also be a limit to their usefulness at the time of labor and delivery to reduce the risk of vertical HIV transmission. The safety and efficacy of these new integrase inhibitors in pregnancy requires more investigation.
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Submitted on : Thursday, August 27, 2020 - 9:54:33 PM
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Lucile Pencolé, Minh Patrick Lê, Florian Bouchet-Crivat, Dominique Duro, Gilles Peytavin, et al.. Placental Transfer of the integrase strand inhibitors cabotegravir and bictegravir in the Ex Vivo Human Cotyledon Perfusion Model. AIDS, Lippincott, Williams & Wilkins, 2020, Online ahead of print. ⟨10.1097/QAD.0000000000002637⟩. ⟨inserm-02924301⟩

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