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

Abstract

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.

Let food be thy medicine. The interaction between ketogenic diet therapy and anti‐seizure medications: A systematic review

“…Although studies addressing CBZ serum levels during KDT are scarce, in the available studies, CBZ levels have been reported to decrease with KDT 20–22 . In a recent case report of a neonate with early onset epilepsy ( SCN2A mutation) which was effectively treated with sodium channel blockers (phenytoin and CBZ) together with KDT, the authors reported a 44% decrease in total CBZ concentrations 35 …”

Pharmacokinetic Drug–Drug Interactions among Antiepileptic Drugs, Including CBD, Drugs Used to Treat COVID-19 and Nutrients

“…A ketogenic diet causes the decrease in the serum concentration of CBZ in young patients (median, 2.91 years), but not significantly [94]. In infants, the ketogenic diet significantly decreased CBZ concentration in 44% during the effective treatment of early onset epilepsy which includes high doses of PHT or CBZ [95].…”

“…There is a very significant dose-dependency of CYP3A4 induction, resulting in a 3-fold increase in CBZ clearance at high PHT doses of 20 mg/kg/day, which increases the concentration-dependent auto-induction of CBZ clearance (2.5-fold at 12 mg/L) [95]. The clearance of busulfan is altered as result of the interaction with PHT and changes in sub or supra concentrations can cause an increase in toxicity [145].…”

Development and evaluation of a simple and easy high‐performance liquid chromatography–ultraviolet system simultaneously suitable for determination of 24 anti‐epileptic drugs in plasma

“…At present, pharmacological treatment with antiepileptic drugs (AEDs) is still a primary selection for most patients. Although the new generation of AEDs has overcome some shortcomings of the "classical" or "first-generation" such as inter-individual variability, narrow therapeutic scopes, nonlinear pharmacokinetics, and serious adverse effects [5,6], however, unpredictable pharmacokinetic interaction of drug-drug or drug-food [7][8][9][10][11] and genetic variation related with drug-metabolizing enzymes or transporters (gene polymorphism) [12] may influence drug serum or plasma concentration, which may further influence drug efficacy or result in adverse effects. In addition, first-generation AEDs such as carbamazepine (CBZ), ethosuximide (ESM), phenobarbital (PHB), phenytoin (PHT), primidone (PRM), and valproic acid are still widely used in primary hospital of China or other developing countries.…”