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

Abstract

BackgroundFetal 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.ObjectiveThe 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.MethodsAn 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.ResultsAn 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).ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0583-8) contains supplementary material, which is available to authorized users.

Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

“…PBPK models constitute another method for investigating placental drug transfer. Various models have previously been presented that allow the prediction of concentrations in the fetal blood or tissues . The 2 most promising approaches for predicting the transfer of a compound across the placenta were those presented by De Sousa Mendes et al and by Zhang et al .…”

Physiologically Based Pharmacokinetic Modeling in Pregnancy: A Systematic Review of Published Models

“…Of note, originating from the Simcyp pregnancy model, more mechanistic PBPK models were recently developed in R, 46,47 MatLab, 40,48 and Berkeley Madonna. 49 Instead of a lumped fetoplacental unit, the models developed in R and MatLab incorporate four separate compartments representing the amniotic fluid, fetal body, fetal blood, and the placenta. The model structure presented by Zhang et al 40,48 can be considered the most detailed to date.…”

Drug Dosing in Pregnant Women: Challenges and Opportunities in Using Physiologically Based Pharmacokinetic Modeling and Simulations

“…Alternative, mechanism‐driven approaches for designing appropriate dosing regimens, and, importantly, to shorten the lag time for newer treatment options (e.g., dolutegravir, elvitegravir, and cobicistat) are highly desirable. This review highlights a case example that demonstrates the utility of physiologically based pharmacokinetic (PBPK) model predictions in selecting the most optimal dose for darunavir/ritonavir, taking into account both maternal and fetal drug exposure …”

“…For antiretroviral agents, similar approaches for incorporating placental transfer and drug disposition in lumped fetal compartments have been described by De Sousa Mendes et al . and Schalkwijk et al . These authors use ex vivo placenta perfusion data obtained from term human placentas in a bottom‐up approach to parameterize the placental passage model parameters with clearance values or rate constants for maternal to fetal transfer and vice versa .…”

“…Specifically, Schalkwijk et al . conducted a follow‐up investigation of the darunavir study by Colbers et al .…”