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

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.