Mammalian Target of Rapamycin Inhibitor Levels Decrease Under Cenobamate Treatment

Abstract

Background: Everolimus therapy has been approved in Tuberous Sclerosis Complex (TSC), for drug-resistant epilepsy as adjunctive therapy. A novel anti-seizure medication is cenobamate, which was approved for adults as adjunctive treatment for focal-onset seizures in drug-resistant epilepsy and is now commonly used in patients with TSC. Drug-drug interactions between cenobamate and mammalian target of rapamycin (mTORi) have not been prospectively evaluated, even though these agents are frequently administered together.

Methods: We performed a retrospective analysis of patients with TSC and compared mTORi drug levels before and after treatment initiation with cenobamate.

Results: We evaluated 20 patients with clinically diagnosed TSC (male: 55%, female: 45%) with a median current age at last visit of 17.0 years (range: 4-41 years, interquartile range [IQR]: 12.5 years). All patients received mTORi treatment of either everolimus (N = 12, 60%) or sirolimus (N = 8, 40%). Cenobamate treatment led to seizure freedom in 2 patients (10%), reduction of seizures in 9 patients (45%) and no change in seizure frequency in 9 patients (45%). Median maximal cenobamate dose was 200 mg (range: 100-500 mg, IQR: 262.5 mg), for example, 3.2 mg/kg/day (range: 0.8-9.5 mg/kg/day, IQR: 3.2 mg/kg/day). Median everolimus levels decreased significantly after cenobamate initiation from 5.1 ng/ml (range: 1.9-11.6 ng/ml, IQR: 3.8 ng/ml) to 3.4 ng/ml (range: 1-7.9 ng/ml, IQR: 1.7 ng/ml, P = 0.01221). The median sirolimus level did not decrease significantly (P = 0.3828).

Conclusion: Everolimus levels decreased following cenobamate initiation. This is likely due to CYP3A4 induction of cenobamate. We recommend monitoring of serum plasma levels of mTORi co-administered with cenobamate and adjustment of mTORi doses accordingly.

Keywords: Cenobamate; Everolimus; Sirolimus; Tuberous sclerosis complex; mTOR inhibitor.