Placental Transfer of Darunavir in an Ex Vivo Human Cotyledon Perfusion Model

Abstract

cPlacental transfer of the HIV protease inhibitor darunavir was investigated in 5 term human cotyledons perfused with darunavir (1,000 ng/ml) in the maternal to fetal direction. The mean (؎ the standard deviation [SD]) fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 15.0% ؎ 2.1%, and the mean (؎SD) clearance index (darunavir FTR/ antipyrine FTR) was 40.3% ؎ 5.8%. This shows that darunavir crosses the placenta at a relatively low rate, resulting in fetal exposure.T he use of antiretroviral drugs has allowed for a spectacular reduction in mother-to-child transmission (MTCT) of HIV in the industrialized countries, with a current rate of Յ0.5% in France (1, 2). Darunavir is an HIV protease inhibitor (PI) that is increasingly used in combination with other drugs to treat HIV infection. It is now considered a first-line option in pregnant women (3, 4), although few data are available to date on its effects during pregnancy. It is classified by the FDA in pregnancy category C (4), meaning that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in pregnant women. Most of the adverse events described are related to nucleoside reverse transcriptase inhibitors, particularly mitochondrial disease (6) and hematologic or cardiac function toxicities (7), whereas few antiretroviral drugs have shown any relation to the risk of malformations (8). The HIV protease inhibitors are largely well tolerated in utero (9), although there are reports of elevated neonatal bilirubin levels following atazanavir exposure (10) and transient adrenal dysfunction following perinatal lopinavir-ritonavir treatment (11). Determining fetal exposure to a specific drug is important in estimating its potential for preexposure prophylaxis (12), as well as its risk for toxicities in the fetus. Since data from animal studies are difficult to extrapolate to humans due to the differences in placental physiology, human studies are required. There are some data on cord blood concentrations of darunavir at delivery, but these data reflect only a single time point, and larger series are required for population pharmacokinetic modeling (13,14). The ex vivo human cotyledon is an accepted model in which to study and interpret placental transfer (15).The purpose of this study was to investigate the placental transfer of darunavir in the ex vivo human perfused cotyledon.Placentas were collected after uneventful pregnancies and term deliveries (Ն37 weeks gestational age) in a single center (a university hospital maternity department in Colombes, France) and were rapidly perfused on site. Written informed consent was obtained from each woman who donated a placenta, according to French bioethics guidelines (article L1211-2 of the Public Health Code).The darunavir base was provided by the manufacturer (Janssen, Issy-les-Moulineaux, France) as antipyrine-phosphate-buffered saline (PBS). Bradford reagent was purchased from SigmaAldrich (Saint Quentin Fallav...

Prediction of Fetal Darunavir Exposure by Integrating Human Ex-Vivo Placental Transfer and Physiologically Based Pharmacokinetic Modeling

“…Maternal-to-fetal (MTF) transfer of darunavir has been previously studied with the ex-vivo cotyledon perfusion model [ 19 ]. In contrast to this study, we included ritonavir and evaluated MTF and fetal-to-maternal (FTM) placental darunavir transfer to account for the potential interaction with placental drug transporters [ 20 ].…”

Placental Transfer of Rilpivirine in an Ex Vivo Human Cotyledon Perfusion Model

“…There are considerable differences in placental transfer rates among the various antiretroviral drugs, which are partly but not entirely related to the class, defined as the site at which they inhibit viral replication. The CLI values reported using this ex vivo placental perfusion model were 40.3% for darunavir (18) and 73% for lopinavir at a 2% serum albumin concentration (19), whereas there was nearly no placental transfer for saquinavir (10). For the nucleoside reverse transcriptase inhibitors, the fetal concentrations were equal to or higher than the maternal concentrations (20), whereas the CLI of the CCR5 inhibitor maraviroc was 26%, and the fusion inhibitor enfuvirtide did not cross the placenta (21).…”

Placental transfer and tissue accumulation of dolutegravir in the ex vivo human cotyledon perfusion model

“…The target was to obtain, after dilution in the maternal compartment, concentrations for the active drug as observed in adults taking dolutegravir 50 mg once daily, where Cmax is on the order of 3000 ng/mL [19]. Experiments were conducted as described previously [20–23]. Perfusates were prepared with Earle’s Balanced Salt Solution, with the addition of human albumin at 2 g/liter (Ydrabulmin 20%, LFB-Biomedicament, Courtaboeuf, France).…”