Estimating fetal exposure to the P-gp substrates, corticosteroids, by PBPK modeling to inform prevention of neonatal respiratory distress syndrome.

We have previously developed a maternal-fetal physiologically-based pharmacokinetic (m-f PBPK) model to dynamically predict (and verify) fetal-maternal exposure to drugs that passively diffuse across the placenta. Here, we extended the application of this model to dynamically predict fetal exposure to drugs which are effluxed by placental P-glycoprotein, namely the antenatal corticosteroids (ACS; dexamethasone [DEX], and betamethasone [BET]). To do so, we estimated both the placental P-gp mediated efflux clearance (CL) and the passive diffusion CL of the ACS. The efficacy and toxicity of the currently used maternal ACS dosing regimens to prevent neonatal respiratory distress syndrome could be improved by altering their dosing regimens. Therefore, to illustrate the utility of our m-f PBPK model, we used it to design alternative dosing regimens of DEX and BET that could potentially improve their efficacy and reduce their toxicity. The redesigned dosing regimens are convenient to administer, maintain maternal-fetal exposure (area under the concentration-time curve [AUC]) or maximum plasma concentration (C ) or both (DEX and BET) or minimize maternal exposure while maintaining fetal drug plasma concentrations above the minimum therapeutic threshold of 1 ng/ml for 48 h (BET only; based on efficacy data in sheep). To our knowledge, this is the first study to dynamically predict fetal plasma concentrations of placental P-gp effluxed drugs. Our approach and our m-f PBPK model could be used in the future to predict maternal-fetal exposure to any drug and to design alternative dosing regimens of the drug.