Predicting Maternal-Fetal Disposition of Fentanyl following Intravenous and Epidural Administration Using Physiologically Based Pharmacokinetic Modeling

Abstract

Fentanyl is an opioid analgesic used to treat obstetrical pain in parturient women through epidural or intravenous route, and unfortunately can also be abused by pregnant women. Fentanyl is known to cross the placental barrier, but how the route of administration and time after dosing affects maternal-fetal disposition kinetics at different stages of pregnancy is not well characterized. To address this knowledge gap, we developed a maternal-fetal physiologically based pharmacokinetic (mf-PBPK) model for fentanyl to evaluate the feasibility to predict the maternal and fetal plasma concentration-time profiles of fentanyl after various dosing regimens. As fentanyl is typically given via the epidural route to control labor pain, an epidural dosing site was developed using alfentanil as a reference drug and extrapolated to fentanyl. Fetal hepatic clearance of fentanyl was predicted from CYP3A7-mediated norfentanyl formation in fetal liver microsomes (intrinsic clearance 5 0.20 ± 0.05 ml/ min/mg protein). The developed mf-PBPK model successfully captured fentanyl maternal and umbilical cord concentrations after epidural dosing and was used to simulate the concentrations after intravenous dosing (in a drug abuse situation). The distribution kinetics of fentanyl were found to have a considerable impact on the time course of maternal:umbilical cord concentration ratio and on interpretation of observed data. The data show that mf-PBPK modeling can be used successfully to predict maternal disposition, transplacental distribution, and fetal exposure to fentanyl.