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Drug–Drug Interactions of Cenobamate With Medications: Dose‐Dependent Induction/Inhibition and Clinical Implications

Year: 2026

Type: article

Abstract: Cenobamate causes dose-dependent cytochrome P450 (CYP)2B6 and CYP3A4 induction and CYP2C19 inhibition, raising concern over multi-pathway drug-drug interactions (DDIs) in patients with epilepsy treated with cardiovascular co-medications. We developed a physiologically based pharmacokinetic (PBPK) model for cenobamate and verified it using reported DDIs for cenobamate 200 mg using three probe substrates: bupropion (CYP2B6), midazolam (CYP3A4), and omeprazole (CYP2C19). The verified model predicted exposure changes (area under the curve ratio [AUCR] and maximum concentration [Cmax] ratio with/without cenobamate) for eight drugs, including anticoagulants and antiplatelets (apixaban, cilostazol, clopidogrel, and rivaroxaban), and antihypertensives (amlodipine, bisoprolol, carvedilol, and nifedipine). Regarding anticoagulants and antiplatelets, for apixaban, AUCR/Cmax ratios were 0.78/0.92 (100 mg), 0.71/0.87 (200 mg), and 0.63/0.83 (400 mg), respectively. For cilostazol, parent exposure decreased (0.67/0.85, 0.55/0.77, 0.45/0.70), while the active metabolite OPC-13015 was predicted to increase in Cmax. For clopidogrel, parent exposure was unchanged, but formation of 2-oxo-clopidogrel and clopidogrel-H4 were decreased and increased, respectively. For rivaroxaban, the AUCR/Cmax ratios were 0.78/0.90, 0.69/0.85, and 0.61/0.80. Among antihypertensives, amlodipine showed decreased AUCR/Cmax ratios (0.57/0.66, 0.45/0.55, 0.37/0.47). The exposure changes of bisoprolol were minor (AUCR 0.84-0.92, Cmax ratio 0.95-0.98); AUCR/Cmax ratios of carvedilol fell to 0.73/0.80, 0.63/0.71, and 0.55/0.64; and nifedipine decreased markedly (0.41/0.54, 0.29/0.41, 0.21/0.32). In conclusion, cenobamate induced CYP2B6 weakly and CYP3A4 moderately, and it inhibited CYP2C19 moderately to drive dose-dependent decreases in exposure for seven of eight drugs with minimal change for bisoprolol. The verified PBPK framework enables risk assessment in scenarios not yet clinically tested.

Source: CPT Pharmacometrics & Systems Pharmacology

DOI: 10.1002/psp4.70358