A PBPK model to predict disposition of CYP3A-metabolized drugs in pregnant women: Verification and discerning the site of CYP3A induction

Besides logistical and ethical concerns, evaluation of safety and efficacy of medications in pregnant women is complicated by marked changes in pharmacokinetics (PK) of drugs. For example, CYP3A activity is induced during the third trimester (T(3)). We explored whether a previously published physiologically based pharmacokinetic (PBPK) model could quantitatively predict PK profiles of CYP3A-metabolized drugs during T(3), and discern the site of CYP3A induction (i.e., liver, intestine, or both). The model accounted for gestational age-dependent changes in maternal physiological function and hepatic CYP3A activity. For model verification, mean plasma area under the curve (AUC), peak plasma concentration (C(max)), and trough plasma concentration (C(min)) of midazolam (MDZ), nifedipine (NIF), and indinavir (IDV) were predicted and compared with published studies. The PBPK model successfully predicted MDZ, NIF, and IDV disposition during T(3). A sensitivity analysis suggested that CYP3A induction in T(3) is most likely hepatic and not intestinal. Our PBPK model is a useful tool to evaluate different dosing regimens during T(3) for drugs cleared primarily via CYP3A metabolism