Drug-drug and drug-food interactions in an infant with early-onset SCN2A epilepsy treated with carbamazepine, phenytoin and a ketogenic diet.

Sodium channel 2 subunit α (SCN2A) mutations cause difficult-to-treat early-onset epilepsy. Effective treatment includes high-dose phenytoin or carbamazepine ± ketogenic diet (KD). We describe an infant with early-onset SCN2A-epilepsy with subtherapeutic carbamazepine concentration during transition from phenytoin treatment to avoid long-term neurotoxicity. The transition from high-dose phenytoin (20 mg kg-1 d-1 , concentration: ≥20 mg/L) with KD, to carbamazepine (50-75 mg kg-1 d-1 , concentration: 9-12 mg/L) lasted 85 days, which we suspected was due to significant drug-drug and/or drug-food interactions. Model-based analysis of carbamazepine pharmacokinetics quantified significant time- and dose-dependent phenytoin-mediated CYP3A4 induction and carbamazepine concentration-dependent auto-induction (apparent clearance increased up to 2.5/3-fold). Lower carbamazepine concentrations under KD were modelled as decreased relative bioavailability (44%), potentially related to decreased fraction absorbed (unexpected for this lipophilic drug), increased intestinal/hepatic metabolism and/or decreased protein-binding with KD. This suggests importance of carbamazepine-concentration monitoring during KD-introduction/removal and necessity of high carbamazepine doses to achieve therapeutic concentrations, especially in infants treated with high-dose phenytoin.