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Laurent Mandelbrot - One of the best experts on this subject based on the ideXlab platform.
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Placental Transfer of the integrase strand inhibitors cabotegravir and bictegravir in the ex vivo human cotyledon perfusion model
AIDS, 2020Co-Authors: Lucile Pencole, Gilles Peytavin, Dominique Duro, Florian Bouchetcrivat, Laurent MandelbrotAbstract:: 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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Placental Transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019
American Journal of Obstetrics & Gynecology MFM, 2020Co-Authors: Margaux Louchet, Jean-marc Tréluyer, Gilles Peytavin, Jeanne Sibiude, Olivier Picone, Laurent MandelbrotAbstract:OBJECTIVE: Treatment of coronavirus disease 2019 is mostly symptomatic, but a widerange of medications are under investigation against severe acute respiratory syndrome coronavirus 2. Although pregnant women are excluded from clinical trials, they willinevitably receive therapies whenever they seem effective in nonpregnant patients andeven under compassionate use. METHODS: We conducted a review of the literature on Placental Transfer and pregnancy safety data of drugs under current investigation for coronavirus disease 2019. RESULTS: Regarding remdesivir, there are no data in pregnant women. Several other candidates already have safety data in pregnant women, because they are repurposed drugs already used for their established indications. Thus, they may be used in pregnancy, although their safety in the context of coronavirus disease 2019 may differ from conventional use. These include HIV protease inhibitors such as lopinavir/ritonavir that have low Placental Transfer, interferon that does not cross the Placental barrier, and hydroxychloroquine or chloroquine that has high Placental Transfer. There are also pregnancy safety and Placental Transfer data for colchicine, steroids, oseltamivir, azi-thromycin, and some monoclonal antibodies. However, some drugs are strictly prohibitedin pregnancy because of known teratogenicity (thalidomide) or fetal toxicities (renin-angiotensin system blockers). Other candidates including tocilizumab, other interleukin 6 inhibitors, umifenovir, and favipiravir have insufficient data on pregnancy outcomes. CONCLUSION: In life-threatening cases of coronavirus disease 2019, the potential risks of therapy to the fetus may be more than offset by the benefit of curing the mother. Although preclinical and Placental Transfer studies are required for a number of potentialanti-severe acute respiratory syndrome coronavirus 2 drugs, several medications can already be used in pregnant women.
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Placental Transfer of elvitegravir and cobicistat in an ex vivo human cotyledon double perfusion model
AIDS, 2017Co-Authors: Valentine Faurebardon, Dominique Duro, Laurent Mandelbrot, Chloé DussauxAbstract:OBJECTIVE To determine the transPlacental pharmacokinetics of the HIV integrase strand Transfer inhibitor elvitegravir and of cobicistat, a cytochrome P450 inhibitor used as a pharmacoenhancer in antiretroviral therapy. DESIGN AND METHODS Maternal-to-fetal Transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in seven open-circuit experiments and 10 closed-circuit (recirculating) experiments. Elvitegravir and cobicistat were added to a maternal perfusate containing 2 g/l of human serum albumin and antipyrine, as a marker to validate the cotyledon's viability. Elvitegravir and cobicistat concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. RESULTS For elvitegravir, in open-circuit experiments the mean (±SD) fetal Transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 19 ± 13% and the mean clearance index was 0.46 ± 0.21; in the closed-circuit model, after 3 h of perfusion the FTR was 20 ± 10% and the mean accumulation index was 12.28 ± 5.57. For cobicistat, in the open perfusions the FTR was 23 ± 13% and the mean clearance index was 0.63 ± 0.34; in the closed perfusions after 3 h the fetal-to-maternal ratio of cobicistat was 21 ± 11%. The mean accumulation index was 3.46 ± 2.19 CONCLUSION:: The two models concurred to show moderate Placental Transfer of elvitegravir and cobicistat across the placenta as well as elvitegravir accumulation in the placenta tissue. Whether this may lead to toxicities and modifications in fetal or Placental metabolism requires clinical studies.
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erratum for mandelbrot et al Placental Transfer of rilpivirine in an ex vivo human cotyledon perfusion model
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Laurent Mandelbrot, Dominique Duro, Emilie Belissa, Gilles PeytavinAbstract:Volume 59, no. 5, p. [2901–2903][1], 2015. Page 2902: In [Table 1][2], the placenta 6 CM and CF values were inadvertently repeated for placenta 7. The table should appear as shown below. View this table: TABLE 1 Placental Transfer of rilpivirine in ex vivo -perfused human cotyledons [1]: /
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Placental Transfer of darunavir in an ex vivo human cotyledon perfusion model
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Laurent Mandelbrot, Dominique Duro, Emilie Belissa, Gilles PeytavinAbstract:Placental 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.
Gilles Peytavin - One of the best experts on this subject based on the ideXlab platform.
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Placental Transfer of the integrase strand inhibitors cabotegravir and bictegravir in the ex vivo human cotyledon perfusion model
AIDS, 2020Co-Authors: Lucile Pencole, Gilles Peytavin, Dominique Duro, Florian Bouchetcrivat, Laurent MandelbrotAbstract:: 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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Placental Transfer of letermovir maribavir in the ex vivo human cotyledon perfusion model new perspectives for in utero treatment of congenital cytomegalovirus infection
PLOS ONE, 2020Co-Authors: Valentine Faure Bardon, Gilles Peytavin, Minh P Le, Tiffany Guilleminot, Elisabeth Elefant, J Stirnemann, Marianne LeruezvilleAbstract:Background Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment. Methods The objective was to investigate the Placental Transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal Transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)). Results For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively. Conclusions Drugs’ concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.
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Placental Transfer of Letermovir & Maribavir in the ex vivo human cotyledon perfusion model. New perspectives for in utero treatment of congenital cytomegalovirus infection.
PloS one, 2020Co-Authors: Valentine Faure Bardon, Gilles Peytavin, Tiffany Guilleminot, Elisabeth Elefant, J Stirnemann, Marianne Leruez-ville, Yves VilleAbstract:Background Congenital cytomegalovirus infection can lead to severe sequelae. When fetal infection is confirmed, we hypothesize that fetal treatment could improve the outcome. Maternal oral administration of an effective drug crossing the placenta could allow fetal treatment. Letermovir (LMV) and Maribavir (MBV) are new CMV antivirals, and potential candidates for fetal treatment. Methods The objective was to investigate the Placental Transfer of LMV and MBV in the ex vivo method of the human perfused cotyledon. Term placentas were perfused, in an open-circuit model, with LMV or MBV at concentrations in the range of clinical peak plasma concentrations. Concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. Mean fetal Transfer rate (FTR) (fetal (FC) /maternal concentration), clearance index (CLI), accumulation index (AI) (retention of each drug in the cotyledon tissue) were measured. Mean FC were compared with half maximal effective concentrations of the drugs (EC50(LMV) and EC50(MBV)). Results For LMV, the mean FC was (± standard deviation) 1.1 ± 0.2 mg/L, 1,000-fold above the EC50(LMV). Mean FTR, CLI and AI were 9 ± 1%, 35 ± 6% and 4 ± 2% respectively. For MBV, the mean FC was 1.4 ± 0.2 mg/L, 28-fold above the EC50(MBV). Mean FTR, CLI and AI were 10 ± 1%, 50 ± 7% and 2 ± 1% respectively. Conclusions Drugs’ concentrations in the fetal side should be in the range for in utero treatment of fetuses infected with CMV as the mean FC was superior to the EC50 for both molecules.
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Placental Transfer and safety in pregnancy of medications under investigation to treat coronavirus disease 2019
American Journal of Obstetrics & Gynecology MFM, 2020Co-Authors: Margaux Louchet, Jean-marc Tréluyer, Gilles Peytavin, Jeanne Sibiude, Olivier Picone, Laurent MandelbrotAbstract:OBJECTIVE: Treatment of coronavirus disease 2019 is mostly symptomatic, but a widerange of medications are under investigation against severe acute respiratory syndrome coronavirus 2. Although pregnant women are excluded from clinical trials, they willinevitably receive therapies whenever they seem effective in nonpregnant patients andeven under compassionate use. METHODS: We conducted a review of the literature on Placental Transfer and pregnancy safety data of drugs under current investigation for coronavirus disease 2019. RESULTS: Regarding remdesivir, there are no data in pregnant women. Several other candidates already have safety data in pregnant women, because they are repurposed drugs already used for their established indications. Thus, they may be used in pregnancy, although their safety in the context of coronavirus disease 2019 may differ from conventional use. These include HIV protease inhibitors such as lopinavir/ritonavir that have low Placental Transfer, interferon that does not cross the Placental barrier, and hydroxychloroquine or chloroquine that has high Placental Transfer. There are also pregnancy safety and Placental Transfer data for colchicine, steroids, oseltamivir, azi-thromycin, and some monoclonal antibodies. However, some drugs are strictly prohibitedin pregnancy because of known teratogenicity (thalidomide) or fetal toxicities (renin-angiotensin system blockers). Other candidates including tocilizumab, other interleukin 6 inhibitors, umifenovir, and favipiravir have insufficient data on pregnancy outcomes. CONCLUSION: In life-threatening cases of coronavirus disease 2019, the potential risks of therapy to the fetus may be more than offset by the benefit of curing the mother. Although preclinical and Placental Transfer studies are required for a number of potentialanti-severe acute respiratory syndrome coronavirus 2 drugs, several medications can already be used in pregnant women.
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erratum for mandelbrot et al Placental Transfer of rilpivirine in an ex vivo human cotyledon perfusion model
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Laurent Mandelbrot, Dominique Duro, Emilie Belissa, Gilles PeytavinAbstract:Volume 59, no. 5, p. [2901–2903][1], 2015. Page 2902: In [Table 1][2], the placenta 6 CM and CF values were inadvertently repeated for placenta 7. The table should appear as shown below. View this table: TABLE 1 Placental Transfer of rilpivirine in ex vivo -perfused human cotyledons [1]: /
Laurent Gavard - One of the best experts on this subject based on the ideXlab platform.
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Placental Transfer of maraviroc in an ex vivo human cotyledon perfusion model and influence of abc transporter expression
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Cecile Vinot, E Courbon, Laurent Gavard, Sebastien Manceau, Jean-marc Tréluyer, Jean Michel Scherrmann, Xavier DeclevesAbstract:Nowadays, antiretroviral therapy is recommended during pregnancy to prevent mother-to-child transmission of HIV. However, for many antiretroviral drugs, including maraviroc, a CCR5 antagonist, very little data exist regarding Placental Transfer. Besides, various factors may modulate this Transfer, including efflux transporters belonging to the ATP-binding cassette (ABC) transporter superfamily. We investigated maraviroc Placental Transfer and the influence of ABC transporter expression on this Transfer using the human cotyledon perfusion model. Term placentas were perfused ex vivo for 90 min with maraviroc (600 ng/ml) either in the maternal-to-fetal (n = 10 placentas) or fetal-to-maternal (n = 6 placentas) direction. Plasma concentrations were determined by ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fetal Transfer rates (FTR) and clearance indexes (CLI) were calculated as ratios of fetal to maternal concentrations at steady state (mean values between 30 and 90 min) and ratios of FTR of maraviroc to that of antipyrine, respectively. ABC transporter gene expression levels were determined by quantitative reverse transcription (RT)-PCR and ABCB1 protein expression by Western blotting. For the maternal-to-fetal direction, the mean FTR and CLI were 8.0% ± 3.0 and 0.26 ± 0.07, respectively, whereas the mean CLI was 0.52 ± 0.23 for the fetal-to-maternal direction. We showed a significant inverse correlation between maraviroc CLI and ABCC2, ABCC10, and ABCC11 Placental gene expression levels (P < 0.05). To conclude, we report a low maraviroc Placental Transfer probably involving ABC efflux transporters and thus in all likelihood associated with a limited fetal exposition. Nevertheless, these results would need to be supported by in vivo data obtained from paired maternal and cord blood samples.
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contribution and limit of the model of perfused cotyledon to the study of Placental Transfer of drugs example of a protease inhibitor of hiv nelfinavir
European Journal of Obstetrics & Gynecology and Reproductive Biology, 2009Co-Authors: Laurent Gavard, Laurent Mandelbrot, Gilles Peytavin, Robert Farinotti, Delphine Beghin, F Forestier, Yvon Cayre, Sophie GilAbstract:Abstract Objectives The perfused cotyledon model is a very useful method to study Placental Transfer of drugs. Here we studied Placental Transfer of the human immunodeficiency virus protease inhibitor nelfinavir using the non-recirculating dual human Placental perfusion with a main goal to determining the clearance index of nelfinavir as related to maternal concentrations, and analyze the conditions under which ex vivo and in vivo data can be correlated. Study design Thirteen human cotyledons, obtained after uneventful term pregnancies, were perfused in an open double circuit with nelfinavir (320–4436μg/l) and a freely diffusing marker antipyrine 20mg/l, in the presence of an albumin concentration of 2g/l. Drug concentrations were determined by high-performance liquid chromatography. Results The mean clearance index of nelfinavir was very weak when maternal concentrations were under 500μg/l (0.03±0.05). For maternal concentrations above 1200μg/l, the mean fetal Transfer rate was 14±3.4%, the mean clearance index was 0.39±0.10 and the fetal concentrations were between 133 and 671μg/l. There was a good correlation between maternal and fetal concentrations ( r =0.86; p Conclusions Our study with nelfinavir has achieved a good correlation between ex vivo and in vivo data. Our results also indicate that studies must be conducted under well defined conditions to obtain accurate and comparable data, underlining the fact that the ex vivo perfused cotyledon remains difficult to standardize as a model system.
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Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model
Hindawi Limited, 2009Co-Authors: Pierre-françois Ceccaldi, Laurent Gavard, Jean-marc Tréluyer, Laurent Mandelbrot, Robert Farinotti, Elisabeth Rey, Sophie GilAbstract:Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on Placental Transfer of lopinavir with ritonavir at different albumin concentrations. Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases. Results. In the control phase, the clearance index of lopinavir decreased from 0.401 ± 0.058 to 0.007 ± 0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95% of CI difference [−0.156, −0.002], P=.046) and became positive for ritonavir. Conclusions. Even at high albumin concentrations, inhibition of Placental P-glycoprotein increased Placental Transfer of lopinavir, suggesting that this efflux pump actively reduces Placental Transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy
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Research Article Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model
2009Co-Authors: Pierre-françois Ceccaldi, Laurent Gavard, Jean-marc Tréluyer, Laurent M, Robert Farinotti, Elisabeth Rey, Sophie GilAbstract:Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on Placental Transfer of lopinavir with ritonavir at different albumin concentrations. Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases. Results. In the control phase, the clearance index of lopinavir decreased from 0.401 ± 0.058 to 0.007 ± 0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95 % of CI difference [−0.156, −0.002], P =.046) and became positive for ritonavir. Conclusions. Even at high albumin concentrations, inhibition of Placental P-glycoprotein increased Placental Transfer of lopinavir, suggesting that this efflux pump actively reduces Placental Transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy. Copyright © 2009 Pierre-Francois Ceccaldi et al. This is an open access article distributed under the Creative Common
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Placental Transfer of enfuvirtide in the ex vivo human placenta perfusion model
American Journal of Obstetrics and Gynecology, 2008Co-Authors: Pierre-françois Ceccaldi, Claudia Ferreira, Laurent GavardAbstract:Objective The objective of the study was to determine the Placental Transfer of the antiretroviral fusion inhibitor, enfuvirtide (Fuzeon). Study Design Human cotyledons were perfused for 90 minutes in an open dual circuit with enfuvirtide, and fetal venous samples were collected every 5 minutes. Three perfusion experiments were validated using antipyrine. Results Enfuvirtide was not detected in the fetal compartment in any of the 3 experiments. The mean concentration of the drug measured in the maternal compartment was 12,400 ng/mL (range, 6500-16,200 ng/mL), which is 2.5 times the maximum concentration recommended for patients treated with enfuvirtide. Conclusion Even at maternal concentrations twice above therapeutic levels, no Placental Transfer of enfuvirtide was observed. The high molecular weight of the molecule (4492 kDa) and its ionized state may account for the lack of Placental Transfer. This result suggests that enfuvirtide could be used in HIV-infected pregnant women without causing fetal exposure.
Dominique Duro - One of the best experts on this subject based on the ideXlab platform.
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Placental Transfer of the integrase strand inhibitors cabotegravir and bictegravir in the ex vivo human cotyledon perfusion model
AIDS, 2020Co-Authors: Lucile Pencole, Gilles Peytavin, Dominique Duro, Florian Bouchetcrivat, Laurent MandelbrotAbstract:: 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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Placental Transfer of elvitegravir and cobicistat in an ex vivo human cotyledon double perfusion model
AIDS, 2017Co-Authors: Valentine Faurebardon, Dominique Duro, Laurent Mandelbrot, Chloé DussauxAbstract:OBJECTIVE To determine the transPlacental pharmacokinetics of the HIV integrase strand Transfer inhibitor elvitegravir and of cobicistat, a cytochrome P450 inhibitor used as a pharmacoenhancer in antiretroviral therapy. DESIGN AND METHODS Maternal-to-fetal Transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in seven open-circuit experiments and 10 closed-circuit (recirculating) experiments. Elvitegravir and cobicistat were added to a maternal perfusate containing 2 g/l of human serum albumin and antipyrine, as a marker to validate the cotyledon's viability. Elvitegravir and cobicistat concentrations were measured using ultraperformance liquid chromatography coupled with tandem mass spectrometry. RESULTS For elvitegravir, in open-circuit experiments the mean (±SD) fetal Transfer rate (FTR) (fetal/maternal concentration at steady state from 30 to 90 min) was 19 ± 13% and the mean clearance index was 0.46 ± 0.21; in the closed-circuit model, after 3 h of perfusion the FTR was 20 ± 10% and the mean accumulation index was 12.28 ± 5.57. For cobicistat, in the open perfusions the FTR was 23 ± 13% and the mean clearance index was 0.63 ± 0.34; in the closed perfusions after 3 h the fetal-to-maternal ratio of cobicistat was 21 ± 11%. The mean accumulation index was 3.46 ± 2.19 CONCLUSION:: The two models concurred to show moderate Placental Transfer of elvitegravir and cobicistat across the placenta as well as elvitegravir accumulation in the placenta tissue. Whether this may lead to toxicities and modifications in fetal or Placental metabolism requires clinical studies.
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Placental Transfer of Darunavir in an Ex Vivo Human Cotyledon Perfusion Model
2016Co-Authors: Laurent M, Dominique Duro, Emilie Belissa, Gilles C Peytavinc, Assistance Publique-hôpitaux De Paris, Hôpital Louis Mourier, Service De Gynécologie-obstetrique, Département Hospitalier, Universitaire Risque GrossesseAbstract:Placental 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/mater-nal 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. The use of antiretroviral drugs has allowed for a spectacularreduction inmother-to-child transmission (MTCT) ofHIV in the industrialized countries, with a current rate of 0.5 % 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 cate-gory C (4), meaning that animal studies have failed to demon-strate a risk to the fetus, but there have been no adequate and well-controlled studies in pregnant women. Most of the advers
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erratum for mandelbrot et al Placental Transfer of rilpivirine in an ex vivo human cotyledon perfusion model
Antimicrobial Agents and Chemotherapy, 2015Co-Authors: Laurent Mandelbrot, Dominique Duro, Emilie Belissa, Gilles PeytavinAbstract:Volume 59, no. 5, p. [2901–2903][1], 2015. Page 2902: In [Table 1][2], the placenta 6 CM and CF values were inadvertently repeated for placenta 7. The table should appear as shown below. View this table: TABLE 1 Placental Transfer of rilpivirine in ex vivo -perfused human cotyledons [1]: /
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Placental Transfer of darunavir in an ex vivo human cotyledon perfusion model
Antimicrobial Agents and Chemotherapy, 2014Co-Authors: Laurent Mandelbrot, Dominique Duro, Emilie Belissa, Gilles PeytavinAbstract:Placental 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.
Pierre-françois Ceccaldi - One of the best experts on this subject based on the ideXlab platform.
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Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model
Hindawi Limited, 2009Co-Authors: Pierre-françois Ceccaldi, Laurent Gavard, Jean-marc Tréluyer, Laurent Mandelbrot, Robert Farinotti, Elisabeth Rey, Sophie GilAbstract:Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on Placental Transfer of lopinavir with ritonavir at different albumin concentrations. Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases. Results. In the control phase, the clearance index of lopinavir decreased from 0.401 ± 0.058 to 0.007 ± 0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95% of CI difference [−0.156, −0.002], P=.046) and became positive for ritonavir. Conclusions. Even at high albumin concentrations, inhibition of Placental P-glycoprotein increased Placental Transfer of lopinavir, suggesting that this efflux pump actively reduces Placental Transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy
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Research Article Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model
2009Co-Authors: Pierre-françois Ceccaldi, Laurent Gavard, Jean-marc Tréluyer, Laurent M, Robert Farinotti, Elisabeth Rey, Sophie GilAbstract:Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on Placental Transfer of lopinavir with ritonavir at different albumin concentrations. Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases. Results. In the control phase, the clearance index of lopinavir decreased from 0.401 ± 0.058 to 0.007 ± 0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95 % of CI difference [−0.156, −0.002], P =.046) and became positive for ritonavir. Conclusions. Even at high albumin concentrations, inhibition of Placental P-glycoprotein increased Placental Transfer of lopinavir, suggesting that this efflux pump actively reduces Placental Transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy. Copyright © 2009 Pierre-Francois Ceccaldi et al. This is an open access article distributed under the Creative Common
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Placental Transfer of enfuvirtide in the ex vivo human placenta perfusion model
American Journal of Obstetrics and Gynecology, 2008Co-Authors: Pierre-françois Ceccaldi, Claudia Ferreira, Laurent GavardAbstract:Objective The objective of the study was to determine the Placental Transfer of the antiretroviral fusion inhibitor, enfuvirtide (Fuzeon). Study Design Human cotyledons were perfused for 90 minutes in an open dual circuit with enfuvirtide, and fetal venous samples were collected every 5 minutes. Three perfusion experiments were validated using antipyrine. Results Enfuvirtide was not detected in the fetal compartment in any of the 3 experiments. The mean concentration of the drug measured in the maternal compartment was 12,400 ng/mL (range, 6500-16,200 ng/mL), which is 2.5 times the maximum concentration recommended for patients treated with enfuvirtide. Conclusion Even at maternal concentrations twice above therapeutic levels, no Placental Transfer of enfuvirtide was observed. The high molecular weight of the molecule (4492 kDa) and its ionized state may account for the lack of Placental Transfer. This result suggests that enfuvirtide could be used in HIV-infected pregnant women without causing fetal exposure.
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Placental Transfer of lopinavir ritonavir in the ex vivo human cotyledon perfusion model
American Journal of Obstetrics and Gynecology, 2006Co-Authors: Laurent Gavard, Claudia Ferreira, Pierre-françois Ceccaldi, Gilles Peytavin, Robert Farinotti, Laurent MandelbrotAbstract:Objective This study was done to determine the Placental Transfer of the human immunodeficiency virus protease inhibitor lopinavir with ritonavir. Study design Twenty-five human cotyledons that were obtained after uneventful pregnancies and deliveries were perfused in an open double circuit with lopinavir (1099-10,606 μg/L) and ritonavir (254-1147 μg/L) at various albumin concentrations (2, 10, and 40 g/L). Results The fetal Transfer rate of lopinavir, when combined with ritonavir, was 23.6% ± 6.9% at an albumin concentration of 2 g/L. The fetal Transfer rate decreased to 20.7% ± 10% at an albumin concentration of 10 g/L and to 3.3% ± 0.5% at an albumin concentration of 40 g/L. Conclusion The Placental Transfer of lopinavir, a highly protein-bound molecule, was compatible with passive diffusion of the unbound fraction. Even at physiologic maternal albumin concentrations, the amount of drug Transferred into the fetal compartment was well above the 50% inhibitory concentration.
