Placental Transfer of Maraviroc in an
            <i>Ex Vivo</i>
            Human Cotyledon Perfusion Model and Influence of ABC Transporter Expression

Vinot, Cécile; Gavard, Laurent; Tréluyer, Jean‐Marc; Manceau, Sandra; Courbon, E.; Scherrmann, Jean‐Michel; Declèves, Xavier; Duro, Dominique; Peytavin, Gilles; Mandelbrot, Laurent; Giraud, C

doi:10.1128/aac.01821-12

Cited by 34 publications

(27 citation statements)

References 48 publications

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“…Placentas were perfused according to a method adapted from Schneider et al (9), as previously described (10)(11)(12). Each perfusion was started within 20 min after delivery.…”

Section: Rilpivirine (4-[[4-[[4-[(e)-2-cyanoethenyl]-26-dimethylphenmentioning

confidence: 99%

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

Mandelbrot

Duro

Belissa

et al. 2015

Antimicrob Agents Chemother

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e Placental transfers of the HIV nonnucleoside reverse transcriptase inhibitor rilpivirine were investigated in 8 term human cotyledons perfused with rilpivirine (400 ng/ml) in the maternal-to-fetal direction. The mean fetal transfer rate (FTR) (fetal/maternal concentration at steady state from 15 to 90 min) was 26% ؎ 8% (mean ؎ standard deviation), and the clearance index (rilpivirine FTR/antipyrine FTR) was 61% ؎ 20%. This shows that rilpivirine crosses the placenta at a relatively high rate, suggesting that the fetus is exposed to the compound during treatment of the mother.A ntiretroviral drugs are remarkably effective for preventing vertical transmission of HIV-1, resulting in a decline in the rate of transmission, which is now less than 0.5% in France (1, 2). Current guidelines recommend antiretroviral therapy for all HIVinfected pregnant women for their own health and to prevent transmission (3, 4)., a diarylpyrimidine analog, is a nonnucleoside reverse transcriptase inhibitor (NNRTI) which is increasingly used to treat HIV infection and in recent guidelines is considered a first-line treatment. It is available in a single-tablet formulation in combination with tenofovir and emtricitabine (Complera-Eviplera). Rilpivirine is classified as a pregnancy category B drug by the Food and Drug Administration (4), which means that animal studies have failed to demonstrate a risk to the fetus, but there have been no adequate and well-controlled studies in HIV-1-infected pregnant women. To date, only one report has been published on two cases of rilpivirine use in pregnant women (5), in which the plasma concentrations of rilpivirine were lower than would be expected in nonpregnant women. Placental transfer was studied in one of these two cases. Currently, there are no data on the safety of rilpivirine use during pregnancy.Determining fetal exposure is important for all new medications in order to estimate the potential for preexposure prophylaxis and the risk for toxicities to the fetus. A number of adverse events have been reported following perinatal exposure to antiretroviral medications, including mitochondrial diseases (6). Since data from animal studies are difficult to extrapolate to humans due to differences in placental physiology, other preclinical approaches are required.The ex vivo human cotyledon is an accepted model used to study and interpret placental transfer (7,8). The purpose of this study was to investigate the placental transfer of rilpivirine in an ex vivo perfused human cotyledon.Placentas were collected after uncomplicated pregnancy with full-term delivery (Ն37 weeks gestational age) in mothers who were seronegative for HIV and hepatitis B and C viruses and had taken no medication, except for vitamin supplements and perimedullar analgesia. They were collected in a single center, the maternity ward of the Hôpitaux Universitaires Paris-Nord Val de Seine (Colombes, France), and were rapidly perfused on site. Written informed consent was obtained from each of the women who donated a placenta, acc...

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“…Placentas were perfused according to a method adapted from Schneider et al (9), as previously described (10)(11)(12). Each perfusion was started within 20 min after delivery.…”

Section: Rilpivirine (4-[[4-[[4-[(e)-2-cyanoethenyl]-26-dimethylphenmentioning

confidence: 99%

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

Mandelbrot

Duro

Belissa

et al. 2015

Antimicrob Agents Chemother

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“…Enfuvirtide has been evaluated for placental transfer and has not been shown to transfer across the placenta at all [49]. MVC shows low-moderate placental transfer in model systems [50].…”

Section: Entry Inhibitorsmentioning

confidence: 99%

HIV and Pregnancy

Vogler

2014

Curr Treat Options Infect Dis

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“…This study is the first to investigate the bidirectional placental transfer of RLT using the ex vivo human perfusion model, which reproduces the conditions of the third trimester of pregnancy (20). The concordance between the results obtained with the ex vivo placental perfusion model and the C/M ratios has been shown for various antiretroviral agents (21). We are aware that our study lacks power due to the small number of experiments.…”

mentioning

confidence: 93%

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

Vinot

Tréluyer

Giraud

et al. 2016

Antimicrob Agents Chemother

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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...

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Placental Transfer of Maraviroc in an Ex Vivo Human Cotyledon Perfusion Model and Influence of ABC Transporter Expression

Cited by 34 publications

References 48 publications

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

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

HIV and Pregnancy

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

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