Open AccessPlacental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model
Author(s) -
Laurent Mandelbrot,
PierreFrançois Ceccaldi,
Dominique Duro,
Minh Patrick Lê,
Lucile Pencolé,
Gilles Peytavin
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0220323
Subject(s) - dolutegravir , transplacental , cotyledon , ex vivo , fetus , andrology , placenta , fetal circulation , perfusion , pharmacokinetics , in vivo , pharmacology , chemistry , medicine , biology , pregnancy , immunology , human immunodeficiency virus (hiv) , botany , microbiology and biotechnology , viral load , antiretroviral therapy , genetics
Objective To determine the transplacental pharmacokinetics of the HIV integrase inhibitor dolutegravir. Study design Maternal-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. Results After 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%. Conclusion Fetal 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.