Impact of Drug Interactions on Clobazam and N-Desmethylclobazam Concentrations in Pediatric Patients With Epilepsy

Background: Clobazam (CLB) is approved as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients aged 2 years and older. It is converted to an active metabolite N-desmethylclobazam (NCLB) by CYP3A4, which is then broken down to an inactive metabolite by CYP2C19. This study characterizes the impact of CYP3A4 and CYP2C19 drug interactions on CLB and NCLB serum concentrations (Cp) and concentration/dose (Cp/D) ratios in pediatric patients with epilepsy. Methods: This was a retrospective chart review including patients older than 1 month, who received CLB between April 2012 and March 2017. Extracted data included patient demographics, CLB daily dose, CLB and NCLB Cp, calculated CLB and NCLB Cp/Cp and Cp/D ratios, and all concomitant drugs. Results: The study included 995 CLB concentration sets from 302 patients (median age 7.6 years and range 0.2-40.1 years). Pharmacokinetic variability was extensive, as seen by widespread ranges of CLB and NCLB Cp, NCLB/CLB Cp ratio, and 3 Cp/D ratios (CLB, NCLB, and CLB + NCLB). Comedications, described as CYP3A4 inducers and/or CYP2C19 inhibitors (carbamazepine, eslicarbazepine, felbamate, (fos)phenytoin, oxcarbazepine, pentobarbital, phenobarbital, rufinamide, and topiramate), generally increased NCLB/ CLB Cp ratio (267%-400%), NCLB Cp/D ratio (167%-202%), and CLB + NCLB Cp/D ratio (142%-185%) and decreased CLB Cp/D ratio (47%-76%) compared with a group of concentration sets in patients receiving only neutral comedications (P < 0.025 for all comparisons). Older age was associated with higher Cp/D ratios (mg/kg), indicative of decreased clearance. Conclusions: Pharmacokinetic variability of CLB in pediatric patients is extensive, and it is influenced by drug-drug interactions and age. Therapeutic drug monitoring of CLB and active metabolite NCLB with calculation of various Cp/Cp and Cp/D ratios can provide useful insight into CLB pharmacokinetics and help differentiate between causes of variability.