Quantitative Cytochrome P450 3A4 Induction Risk Assessment Using Human Hepatocytes Complemented with Pregnane X Receptor-Activating Profiles

Ekiciler, Aynur; Chen, Wen Li Kelly; Yan, Bo; Pugliano, Alessandra; Donzelli, Massimiliano; Parrott, Neil; Umehara, Kenichi

doi:10.1124/dmd.122.001132

Cited by 4 publications

(1 citation statement)

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“…To determine these values, we reviewed the induction mechanisms of CBZ on the enzymes in question. CBZ primarily induces CYP3A4 via the pregnane X receptor (PXR) [ 98 , 99 ], as confirmed by the FDA DDI draft guidance [ 28 ]. However, there is some discrepancy in the literature regarding the induction of CYP2C enzymes.…”

Section: Discussionmentioning

confidence: 99%

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

Yin,

Cicali,

Rodriguez-Vera

et al. 2024

Pharmaceutics

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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 AUClast 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.

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Section: Discussionmentioning

confidence: 99%