Clobazam

Absorption

The peak plasma levels (C
max) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10 to 80 mg following single- or multiple-dose administration of clobazam. Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5 to 160 mg/day. Clobazam is converted to N-desmethylclobazam which has about 1/5 the activity of clobazam. The estimated mean elimination half-lives (t½) of clobazam and N-desmethylclobazam were 36 to 42 hours and 71 to 82 hours, respectively.
Absorption
Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (T
max) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single dose administration of the oral suspension under fasted conditions, the T
maxranged from 0.5 to 2 hours. Based on exposure (C
maxand AUC) of clobazam, clobazam tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption.
Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions.
Distribution
Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. The
in vitroplasma protein binding of clobazam and N-desmethylclobazam is approximately 80 to 90% and 70%, respectively.
Metabolism and Excretion
Clobazam is extensively metabolized in the liver, with approximately 2% of the dose recovered in urine and 1% in feces as unchanged drug. The major metabolic pathway of clobazam involves N-demethylation, primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3 to 5 times higher than those of the parent compound. Based on animal and
in vitroreceptor binding data, estimates of the relative potency of N-desmethylclobazam compared to parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively metabolized, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine.
The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N
-desmethylclobazam
[see
Clinical Pharmacology ( 12.5 )
]
. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers.
Pharmacokinetics in Specific Populations
Age
Population pharmacokinetic analyses showed that the clearance of clobazam is lower in elderly subjects compared to other age groups (ages 2 to 64). Dosing should be adjusted in the elderly
[see
Dosage and Administration ( 2.4 )
]
.
Sex
Population pharmacokinetic analyses showed no difference in the clearance of clobazam between women and men.
Race
Population pharmacokinetic analyses including Caucasian (75%), African American (15%), and Asian (9%) subjects showed that there is no evidence of clinically significant effect of race on the clearance of clobazam.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of clobazam was evaluated in patients with mild (creatinine clearance [CL
CR] >50 to 80 mL/min; N=6) and moderate (CL
CR=30 to 50 mL/min; N=6) renal dysfunction, with matching healthy controls (N=6), following administration of multiple doses of clobazam 20 mg/day. There were insignificant changes in C
max(3 to 24%) and AUC (≤13%) for clobazam or …