Dataset Information

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

ABSTRACT: BACKGROUND:Fetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship. OBJECTIVE:The aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term. METHODS:An existing and validated pregnancy physiologically based pharmacokinetic model of maternal darunavir/ritonavir exposure was extended with a feto-placental unit. To parameterize the model, we determined maternal-to-fetal and fetal-to-maternal darunavir/ritonavir placental clearance with an ex-vivo human cotyledon perfusion model. Simulated maternal and fetal pharmacokinetic profiles were compared with observed clinical data to qualify the model for simulation. Next, population fetal pharmacokinetic profiles were simulated for different maternal darunavir/ritonavir dosing regimens. RESULTS:An average (±standard deviation) maternal-to-fetal cotyledon clearance of 0.91 ± 0.11 mL/min and fetal-to-maternal clearance of 1.6 ± 0.3 mL/min was determined (n = 6 perfusions). Scaled placental transfer was integrated into the pregnancy physiologically based pharmacokinetic model. For darunavir 600/100 mg twice a day, the predicted fetal maximum plasma concentration, trough concentration, time to maximum plasma concentration, and half-life were 1.1, 0.57 mg/L, 3, and 21 h, respectively. This indicates that the fetal population trough concentration is higher or around the half-maximal effective darunavir concentration for a resistant virus (0.55 mg/L). CONCLUSIONS:The results indicate that the population fetal exposure after oral maternal darunavir dosing is therapeutic and this may provide benefits to the prevention of mother-to-child transmission of human immunodeficiency virus. Moreover, this integrated approach provides a tool to prevent fetal toxicity or enhance the development of more selectively targeted fetal drug treatments.

SUBMITTER: Schalkwijk S

PROVIDER: S-EPMC5974000 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Schalkwijk Stein S Buaben Aaron O AO Freriksen Jolien J M JJM Colbers Angela P AP Burger David M DM Greupink Rick R Russel Frans G M FGM

Clinical pharmacokinetics 20180601 6

<h4>Background</h4>Fetal antiretroviral exposure is usually derived from the cord-to-maternal concentration ratio. This static parameter does not provide information on the pharmacokinetics in utero, limiting the assessment of a fetal exposure-effect relationship.<h4>Objective</h4>The aim of this study was to incorporate placental transfer into a pregnancy physiologically based pharmacokinetic model to simulate and evaluate fetal darunavir exposure at term.<h4>Methods</h4>An existing and validat ...[more]

PMID: 28744795

Similar Datasets

Project description:BACKGROUND AND OBJECTIVE:Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal-maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. METHODS:An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. RESULTS:Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L. CONCLUSION:The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets