Predicting Human Fetal Drug Exposure Through Maternal-Fetal PBPK Modeling and In Vitro or Ex Vivo Studies

Abstract

Medication (drug) use in human pregnancy is prevalent. Determining fetal safety and efficacy of drugs is logistically challenging. However, predicting (not measuring) fetal drug exposure (systemic and tissue) throughout pregnancy is possible through maternal-fetal physiologically based pharmacokinetic (PBPK) modeling and simulation. Such prediction can inform fetal drug safety and efficacy. Fetal drug exposure can be quantified in 2 complementary ways. First, the ratio of the steady-state unbound plasma concentration in the fetal plasma (or area under the plasma concentration-time curve) to the corresponding maternal plasma concentration (ie, K_p,uu ). Second, the maximum unbound peak (C_u,max,ss,f ) and trough (C_u,min,ss,f ) fetal steady-state plasma concentrations. We (and others) have developed a maternal-fetal PBPK model that can successfully predict maternal drug exposure. To predict fetal drug exposure, the model needs to be populated with drug specific parameters, of which transplacental clearances (active and/or passive) and placental/fetal metabolism of the drug are critical. Herein, we describe in vitro studies in cells/tissue fractions or the perfused human placenta that can be used to determine these drug-specific parameters. In addition, we provide examples whereby this approach has successfully predicted systemic fetal exposure to drugs that passively or actively cross the placenta. Apart from maternal-fetal PBPK models, animal studies also have the potential to estimate fetal drug exposure by allometric scaling. Whether such scaling will be successful is yet to be determined. Here, we review the above approaches to predict fetal drug exposure, outline gaps in our knowledge to make such predictions and map out future research directions that could fill these gaps.

Keywords: in vitro to in vivo extrapolation; maternal-fetal PBPK model; perfused placenta; predicting fetal drug exposure; transfected and placental cell lines; transporters and enzymes.

Figure 1:

(a) Routes by which drugs distribute into or are cleared from the fetal compartment. (b) Expanded view of the placenta with magnification of the syncytiotrophoblast layer and examples of transporters and enzyme expressed there. Abbreviations: CL_PD: passive bi-directional placental clearance; CL_MP: transporter-mediated influx clearance; CL_PM: transporter-mediated efflux clearance; CL_p0: placental metabolic clearance; CL_f0: fetal metabolic clearance; CYPs: cytochrome P450s (CYPs); UGTs: UDP-glucuronosyltransferases; SULTs: sulfotransferases, GSTs: glutathione-S-transferases; MAO: monoamine oxidase; XO: xanthine oxidase; EH: epoxide hydrolase. Details of other transporters and enzymes present in the placenta are provided in Table 1.

Figure 1:

(a) Routes by which drugs distribute into or are cleared from the fetal compartment. (b) Expanded view of the placenta with magnification of the syncytiotrophoblast layer and examples of transporters and enzyme expressed there. Abbreviations: CL_PD: passive bi-directional placental clearance; CL_MP: transporter-mediated influx clearance; CL_PM: transporter-mediated efflux clearance; CL_p0: placental metabolic clearance; CL_f0: fetal metabolic clearance; CYPs: cytochrome P450s (CYPs); UGTs: UDP-glucuronosyltransferases; SULTs: sulfotransferases, GSTs: glutathione-S-transferases; MAO: monoamine oxidase; XO: xanthine oxidase; EH: epoxide hydrolase. Details of other transporters and enzymes present in the placenta are provided in Table 1.

Figure 2:

Prediction of fetal drug exposure using the m-f-PBPK approach combined with data from (a) the ER-REF studies (left panel) or (b) the perfused placenta studies (right panel). Although the perfused placenta approach is shown in a single-pass mode, the re-circulation mode could also be used. CL_u - unbound clearance; CL_int(B→A) and CL_int(A→B) - intrinsic drug clearance in the B→A and the A→B direction, respectively; ER - efflux ratio; P_app(B→A) and P_app(A→B) - apparent drug permeability in the B→A and the A→B direction, respectively; F→M - fetal to maternal; M→F - maternal to fetal; REF - relative expression factor.