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Review
. 2019 Jan;59(1):7-19.
doi: 10.1002/jcph.1313. Epub 2018 Oct 4.

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Dwain Tolbert  1 , Frank Larsen  2
Affiliations
Review

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Dwain Tolbert et al. J Clin Pharmacol. 2019 Jan.

Abstract

Clobazam (CLB) is a 1,5-benzodiazepine that has been widely used as an anxiolytic and antiseizure drug (ASD) since it was first synthesized over 50 years ago. CLB was approved in the United States in 2011 as adjunctive therapy for seizures in patients ≥2 years old with Lennox-Gastaut syndrome. CLB pharmacokinetics (PK) have been studied in single- and multiple-dose administrations in healthy subjects. Salient features include high bioavailability, linear PK, and negligible effects from coadministration of other ASDs. CLB is highly and extensively absorbed, with little effect from food; time to maximum plasma concentration is 0.5 to 4 hours following the dose. After CLB doses of 20 to 40 mg/day, the volume of distribution is 99 to 120 L, with oral clearance ranging from 1.9 to 2.3 L/h. CLB is lipophilic and distributes throughout the body after oral administration. It is metabolized in the liver by cytochrome P450 (CYP) isoenzymes CYP3A, CYP2C19, and CYP2B6, and its main active metabolite is N-desmethylclobazam. The half-life of CLB after a single oral dose ranges from 36 to 42 hours; the half-life of N-desmethylclobazam ranges from 59 to 74 hours. The metabolites of CLB are primarily excreted renally. Population PK modeling using data from healthy subjects and patients with Lennox-Gastaut syndrome indicates that race, sex, age, weight, and renal function do not influence CLB PK. As CLB has been extensively studied since the 1970s, this review is meant to provide a consolidated and comprehensive resource on CLB PK for both prescribers and scientists alike.

Keywords: Lennox-Gastaut syndrome; N-desmethylclobazam; clobazam; drug-drug interactions; pharmacodynamics; pharmacokinetics.

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Figures

Figure 1
Figure 1
Pathways of CLB metabolism in humans. CLB, its major metabolites produced in vivo, and the primary CYP enzymes that mediate biotransformation are shown; the favored first step in the metabolism of CLB is indicated by a thicker arrow. CLB, clobazam; CYP, cytochrome P450.
Figure 2
Figure 2
Mean (± SD) clobazam (A) and N‐desmethylclobazam (B) plasma concentrations following a single oral dose of 20‐mg clobazam suspension (test) or tablet (reference).32 In this randomized, open‐label, 2‐way crossover study, participants received a single dose of 20‐mg CLB oral suspension or tablet on study day 1 and day 15, with an intervening 14‐day washout period. PK parameters were measured from blood samples drawn predose (0 hours) and regularly through 312 hours after dose, quantified via LC‐MS/MS. The panels on the left show the entire time course; the panels on the right show finer detail for the plasma concentrations versus time in the first 24 hours. CLB, clobazam; LC, liquid chromatography; MS, mass spectrometry.
Figure 3
Figure 3
Hepatic function status and apparent clearance rate of CLB (A, B) and N‐CLB (C, D). Note: K40 is equivalent to the clearance rate of N‐CLB because the apparent volume of N‐CLB was fixed at 1 L. CL, clearance; CLB, clobazam; N‐CLB, N‐desmethylclobazam. Reproduced from Tolbert D, Bekersky I, Chu HM, Ette EI. An integrative population pharmacokinetics approach to the characterization of the effect of hepatic impairment on clobazam pharmacokinetics. J Clin Pharmacol. 2016;56(2):213‐222, with permission conveyed through Copyright Clearance Center, Inc.
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