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

Placental transfer of the HIV integrase inhibitor raltegravir (RLT) was investigated in term human cotyledons in the maternal-to-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.

Prediction of human fetal pharmacokinetics using ex vivo human placenta perfusion studies and physiologically based models.

AIMS: Pregnant women can be exposed to numerous drugs during the gestational period. For obvious ethical reasons, in vivo studies of fetal exposure to drugs are limited. Information about the transplacental transfer of drugs prior to their administration to pregnant women would be highly useful. In the present study, a novel approach was developed quantitatively predict or to predict the fetal exposure to drugs administered to the mother quantitatively. METHODS: Transplacental parameters estimated from ex vivo human placenta perfusion experiments were implemented in pregnancy-physiologically based pharmacokinetic (p-PBPK) models in order to predict fetal PK. Thereafter, fetal PK profiles for two antiretroviral drugs, tenofovir (TFV) and emtricitabine (FTC) were simulated. These predictions were then compared to observed cord blood concentrations, to validate these models. RESULTS: Parameters obtained from the ex vivo experiments enabled a good prediction of observed cord blood concentrations without additional a scaling factor. Moreover, a sensitivity analysis showed that fetal predictions were sensitive to changes in transplacental parameters values obtained ex vivo. CONCLUSION: The integration of ex vivo human placental perfusion parameters in a p-PBPK model should be a promising new approach for predicting human fetal exposure to xenobiotics.

Comparative transplacental transfer of taxanes using the human perfused cotyledon placental model.

OBJECTIVES: The use of taxanes (paclitaxel and docetaxel) in pregnant cancer patients is increasing. We aimed to compare their transplacental transfer using the gold standard human placental perfusion model, to guide drug selection. STUDY DESIGN: Term placentas were perfused with paclitaxel or docetaxel and 2 different albumin concentrations. Main transfer parameters such as fetal transfer rate (FTR), clearance index, and placental uptake of taxanes were assessed. RESULTS: Twelve placentas were perfused, 6 with paclitaxel and 6 with docetaxel. Mean FTR of paclitaxel decreased significantly from 5.67 ± 0.02% in low albumin conditions to 1.72 ± 0.09% in physiological albumin conditions. Similarly, mean clearance index decreased significantly from 0.22 ± 0.02 to 0.09 ± 0.01. Regarding docetaxel, mean FTR were similar in low albumin and physiological conditions (5.03 ± 0.60% and 4.04 ± 0.22%, respectively) while mean clearance index decreased significantly from 0.18 ± 0.02 to 0.13 ± 0.01. Taxanes accumulation in cotyledon was similar for docetaxel and paclitaxel: 4.54 ± 1.84% vs 3.31 ± 1.88%, respectively. CONCLUSION: Transplacental transfer and placental accumulation of paclitaxel and docetaxel were low and similar, especially in physiological conditions of albumin. Further studies are warranted to optimize the selection of a taxane in pregnant cancer patients.

Transplacental transfer of oseltamivir and its metabolite using the human perfused placental cotyledon model.

OBJECTIVE: Given the lack of data regarding the use of oseltamivir (Tamiflu) during pregnancy, we aimed to evaluate the placental transfer of oseltamivir phosphate and its active metabolite oseltamivir carboxylate, using the perfused placental cotyledon model. STUDY DESIGN: Cotyledons were coperfused with oseltamivir phosphate and oseltamivir carboxylate using the maximal concentrations described with a 75 mg, twice-daily oral dose. Main transfer parameters such as fetal transfer rate (FTR) and clearance index (CI) were assessed. RESULTS: Five placentas were coperfused with oseltamivir phosphate and oseltamivir carboxylate. The median FTR of oseltamivir phosphate was 8.5% (range, 5.0-11.6%) and the median CI was 0.3 (range, 0.2-0.6). Regarding oseltamivir carboxylate transplacental transfer, the median FTR was 6.6% (range, 3.9-9.7%), whereas the median CI was 0.2 (range, 0.2-0.5). CONCLUSION: A transplacental transfer of oseltamivir phosphate and its metabolite oseltamivir carboxylate was detected and might have clinical relevance. Clinicians should be encouraged to report oseltamivir treatment outcomes during pregnancy.