Bidirectional Transfer of Raltegravir in an Ex Vivo Human Cotyledon Perfusion Model

Abstract

i Placental transfer of the HIV integrase inhibitor raltegravir (RLT) was investigated in term human cotyledons in the maternalto-fetal (n ‫؍‬ 3) and fetal-to-maternal (n ‫؍‬ 6) directions. In the maternal-to-fetal direction, the mean ؎ standard deviation (SD) fetal transfer rate (FTR) was 9.1% ؎ 1.4%, and the mean ؎ SD clearance index (IC), i.e., RLT FTR/antipyrine FTR, was 0.28 ؎ 0.05. In the fetal-to-maternal direction, the mean ؎ SD CI was 0.31 ؎ 0.09. Placental transfer of RLT was high in both directions.A ntiretroviral therapy (ART), in addition to its benefits for the health of people living with HIV, is effective for preventing mother-to-child transmission (MTCT) of HIV-1, which in industrialized countries has been reduced to Ͻ1% (1-3). Raltegravir (RLT) belongs to the integrase strand transfer inhibitor (INSTI) class of antiretroviral agents, which act by blocking the insertion of viral cDNA into human genomic DNA (4). RLT is classified in category C by the Food and Drug Administration (FDA), meaning that fetal risk has been detected in animal reproduction studies, but there have been no adequate studies conducted in pregnant women. The placental transfer of currently used antiretrovirals varies considerably between classes and individual molecules, and nucleoside reverse transcriptase inhibitors (NRTIs) have high placental transfer (5, 6), whereas protease inhibitors have lower placental transfer (7,8). The purpose of this study was to investigate the bidirectional placental transfer of RLT by using the ex vivo model of the human perfused cotyledon.Nine term placentas from normal pregnancies (from 38 to 42 weeks of gestational age) were obtained from Louis Mourier Hospital (Colombes, France). All mothers were seronegative for HIV infection and hepatitis B and C, and they had taken no medication other than oxytocin or epidural anesthesia during labor. Written informed consent was obtained for all placentas. RLT base was provided by Merck (Paris, France), antipyrine-phosphate-buffered saline (PBS) was purchased from Sigma-Aldrich (SaintQuentin-Fallavier, France), and other chemicals were from Invitrogen (Cergy-Pontoise, France).Placentas were perfused in an open double-circuit system, as previously described (9). Perfusion experiments were started within 20 min after delivery. After visual examination, an intact cotyledon was selected, and a truncal branch of the chorionic artery and the associated vein were cannulated; the establishment of venous flow after perfusion of the fetal artery flow confirmed the viability of the cotyledon. On the maternal side, the perfused area progressively whitened, allowing visualization of the cotyledon. The cotyledon was placed into the perfusion chamber and maintained at 37°C, with the maternal side upward. The intervillous space on the maternal side was perfused by two needles piercing the basal plate. The two circuits were pumped separately by peristaltic pumps. The fetal and maternal flows were 6 and 12 ml/min, respectively, and the perfusion length was 90 min. The p...

Placental transfer of xenobiotics in pregnancy physiologically-based pharmacokinetic models: Structure and data

“…Other publications [122][123][124] computed, for a specific period of time (generally up to 90 min), the fetal transfer rate (FTR, ratio of venous fetal concentration of a substance over maternal concentration) and a clearance index (CLI) as the ratio of the FTR of a substance over the FTR of antipyrine (the fetal perfusion rate is not included in CLI computation).…”

Risk of birth defects and perinatal outcomes in HIV-infected women exposed to integrase strand inhibitors during pregnancy

“…The major limitation is the small number of INSTI-exposed pregnancies, in accordance with French national guidelines that favor PI-based therapy for women wishing to become pregnant, thus limiting the power of our analyses. This highlights the importance on maintaining an active research on the possible side effects of any ART given during pregnancy and especially those that have a high placental transfer ratio such as INSTIs [23,24]. Another limitation is that we cannot exclude possible confounding factors that may have not been taken into account, such as viral load and CD4 count at conception, or preexisting conditions and concurrent drugs potentially associated to birth defects as these were not available in our study.…”

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

“…The placental transfer of dolutegravir seems to be higher as compared with the other integrase inhibitors, raltegravir and elvitegravir. For raltegravir, Vinot et al [33] found an FTR in the maternal-to-fetal direction of 9.1% ± 1.4% and a CLI of 0.28 ± 0.05%. For elvitegravir, we have reported in the same closed-circuit model, after 3h of perfusion an FTR of 20% ± 10% [20].…”