Applying Physiologically Based Pharmacokinetic Modeling to Interpret Carbamazepine's Nonlinear Pharmacokinetics and Its Induction Potential on Cytochrome P450 3A4 and Cytochrome P450 2C9 Enzymes.

Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the root causes have not been fully studied. This study aims to investigate the mechanisms behind CBZ's nonlinear PK and its induction potential on CYP3A4 and CYP2C9 enzymes. To achieve this, we developed and validated a physiologically based pharmacokinetic (PBPK) parent-metabolite model of CBZ and its active metabolite Carbamazepine-10,11-epoxide in GastroPlus ® . The model was utilized for Drug-Drug Interaction (DDI) prediction with CYP3A4 and CYP2C9 victim drugs and to further explore the underlying mechanisms behind CBZ's nonlinear PK. The model accurately recapitulated CBZ plasma PK. Good DDI performance was demonstrated by the prediction of CBZ DDIs with quinidine, dolutegravir, phenytoin, and tolbutamide; however, with midazolam, the predicted/observed DDI AUC last ratio was 0.49 (slightly outside of the two-fold range). CBZ's nonlinear PK can be attributed to its nonlinear metabolism caused by autoinduction, as well as nonlinear absorption due to poor solubility. In further applications, the model can help understand DDI potential when CBZ serves as a CYP3A4 and CYP2C9 inducer.