Abstract
Many women take drugs during their pregnancy to treat a variety of clinical conditions. To optimize drug efficacy and reduce fetal toxicity, it is important to determine or predict fetal drug exposure throughout pregnancy. Previously, we developed and verified a maternal-fetal physiologically based pharmacokinetic (m-f PBPK) model to predict fetal Kp,uu (unbound fetal plasma AUC/unbound maternal plasma AUC) of drugs that passively cross the placenta. Here, we used in vitro transport studies in Transwell®, in combination with our m-f PBPK model, to predict fetal Kp,uu of drugs that are effluxed by placental P-glycoprotein (P-gp), namely dexamethasone, betamethasone, darunavir and lopinavir. Using Transwell®, we determined the efflux ratio (ER) of these drugs in hMDR1-MDCKcP-gpKO cells where human P-gp was overexpressed and the endogenous P-gp was knocked-out. Then, using the proteomics-informed efflux ratio-relative expressive factor (ER-REF) approach, we predicted the fetal Kp,uu of these drugs at term. Finally, to verify our predictions, we compared them with the observed in vivo fetal Kp,uu at term. The latter was estimated using our m-f PBPK model and published fetal (umbilical vein, UV)/maternal plasma drug concentrations obtained at term (UV/MP). Fetal Kp,uu predictions for dexamethasone (0.63), betamethasone (0.59), darunavir (0.17) and lopinavir (0.08) were successful as they fell within the 90% confidence interval (CI90%) of the corresponding in vivo fetal Kp,uu (0.30 - 0.66, 0.29 - 0.71, 0.11 - 0.22, 0.04 - 0.19, respectively). This is the first demonstration of successful prediction of fetal Kp,uu of P-gp drug substrates from in vitro studies.
Significance Statement For the first time, using in vitro studies in cells, we successfully predicted human fetal Kp,uu of P-gp substrate drugs. This success confirms that our m-f PBPK model, combined with the ER-REF approach, can successfully predict fetal drug exposure to P-gp substrates. This success provides increased confidence in the use of the ER-REF approach, combined with our m-f PBPK model, to predict fetal Kp,uu of drugs (transported by P-gp or other transporters), both at term and at earlier gestational ages.
- dexamethasone
- drug efficacy
- drug efflux
- efflux transporters (P-gp, BCRP, MRP, MATE, BSEP, etc)
- physiologically-based pharmacokinetic modeling/PBPK
- placenta
- © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.