PREDICTING FETAL EXPOSURE TO DRUGS THROUGHOUT PREGNANCY USING A PBPK MODEL

Abstract

BackgroundPregnant women use medication throughout pregnancy [1]. As a result, their fetuses are de facto exposed to drugs. For logistical and ethical concerns, invasive measurement of fetal exposure to drugs is not possible. Though cord plasma concentrations can be obtained at birth, this is mostly limited to one blood sample and is difficult to interpret as it is highly dependent on timing of the blood sample relative to the maternal drug dosing regimen. In addition, since the fetus is more vulnerable to teratogens during earlier trimesters, it is important that fetal drug exposure be estimated throughout gestation. Recently, we have shown through PBPK modeling and simulation that the disposition of CYP‐metabolized drugs can be predicted in pregnant women [2, 3]. Here we show an expansion of this model to allow prediction of fetal exposure to CYP metabolized drugs that passively diffuse across the placenta.ObjectivesTo 1) expand our previously published maternal pregnancy PBPK to include the fetus (m‐f‐PBPK); 2) populate this model with changes in fetal physiological parameters throughout pregnancy; 3) use the m‐f‐PBPK model to predict the fetal concentrations of model drugs cleared by CYP enzymes (i.e. midazolam by CYP3A and theophylline by CYP1A2) with negligible placental drug transport/metabolism; 4) verify our predictions by comparing the predicted and observed cord and cord: maternal plasma (UV: MP) drug concentrations at the time of birth.MethodsThe original model was expanded to include the fetus. Data from qualified studies on key fetal physiological parameters were compiled, integrated, and analyzed with respect to gestational age. Then, these parameters were incorporated into the m‐f‐PBPK model to simulate maternal and fetal plasma drug concentration‐time (C‐T) profiles for a virtual population (n=100). For the latter, known inter‐individual variability in maternal physiology and ADME processes were generated using the Simcyp® Simulator and incorporated in the m‐f PBPK model. Lastly, we verified the m‐f PBPK model by comparing the predicted and observed plasma drug concentration(s) in the mother and her fetus at the time of labor and delivery [4, 5]. Once verified, we simulated maternal and fetal C‐T profiles of model drugs at various gestational ages.ResultsExcept for the plasma concentrations at a few time points, the majority of the observed maternal, fetal and UV: MP data fell within the 5th and 95th percentile prediction interval from the virtual population. Our sensitivity analysis suggests that fetal C‐T profile and UV: MP ratio can vary significantly with progression of pregnancy due to changes in maternal and fetal placental blood flows as well as plasma albumin concentrations.ConclusionsOur m‐f‐PBPK successfully predicted the maternal and fetal disposition of midazolam and theophylline. We are currently quantifying the expression of drug transporters and enzymes in human placenta and fetal livers to extend this model to predict fetal exposure to drugs that are transported/metabolized by the placenta.Acknowledgement: Supported by NIH grant P01DA032507.Support or Funding InformationSupported by NIH grant P01DA032507.