Predicting fetal exposure of crizotinib during pregnancy: Combining human ex vivo placenta perfusion data with physiologically-based pharmacokinetic modeling

Abstract

Commercially available physiologically-based pharmacokinetic (PBPK) modeling platforms increasingly allow estimations of fetal exposure to xenobiotics. We aimed to explore a physiology-based approach in which literature data from ex vivo placenta perfusion studies are used to parameterize Simcyp's pregnancy-PBPK (p-PBPK) model, taking crizotinib as an example. First, a physiologically-based semi-mechanistic placenta (PBMP) model was developed in MATLAB to analyze placenta perfusion data of crizotinib. Mixed-effects modeling was performed to derive intrinsic unbound clearance values across the maternal-placental barrier and fetal-placental barrier. Values were then used for parameterization of the p-PBPK model. The PBMP model adequately described the perfusion data. Clearance was estimated to be 71 mL/min and 535 mL/min for the maternal placental uptake and efflux, and 8 mL/min and 163 mL/min for fetal placental uptake and efflux, respectively. For oral dosing of 250 mg twice daily, p-PBPK modeling predicted a C_max and AUC_0-τ of 0.08 mg/L and 0.78 mg/L*h in the umbilical vein at steady-state, respectively. In placental tissue, a C_max of 5.04 mg/L was predicted. In conclusion, PBMP model-based data analysis and the associated p-PBPK modeling approach illustrate how ex vivo placenta perfusion data may be used for fetal exposure predictions.

Keywords: Fetal exposure prediction; PBPK modeling; Placental transfer; Quantitative in vitro-in vivo extrapolation; Reproductive toxicology.