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

Russell, Gabrielle R., PharmD*,†; Phelps, Stephanie J., PharmD*; Shelton, Chasity M., PharmD*,†; Wheless, James W., MD‡,†

doi: 10.1097/FTD.0000000000000530
Original Article
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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.

*Department of Clinical Pharmacy and Translational Science, The University of Tennessee Health Science Center, Memphis, Tennessee;

Le Bonheur Children's Hospital, Memphis, Tennessee; and

Department of Pediatric Neurology, The University of Tennessee Health Science Center, Memphis, Tennessee

Correspondence: James W. Wheless, MD, Pediatric Neurology, The University of Tennessee Health Science Center, 49 N Dunlap Avenue, 3rd floor FOB, 355 Le Bonheur Physician's Office Building, Memphis, TN 38103 (e-mail: jwheless@uthsc.edu).

James W. Wheless has received grant support from Lundbeck, Eisai, GlaxoSmithKline, King Pharmaceuticals, Supernus, The Shainberg Foundation, and the National Institutes of Health. He has served as a consultant to Lundbeck, Cyberonics, Pfizer, Eisai, and Sunovion and has received speaking fees from Lundbeck, Questcor, Cyberonics, and Eisai. The remaining authors have no conflicts of interests to disclose.

Received February 22, 2018

Accepted April 13, 2018

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.