The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N‐desmethylclobazam.

Pullar, T; Edwards, Dearborn; Haigh, J. R. M.; Peaker, S.; Feely, M.

doi:10.1111/j.1365-2125.1987.tb03051.x

Cited by 20 publications

(14 citation statements)

References 17 publications

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“…CBZ and CLB are both metabolized by oxidative pathways, which can be induced by the concomitant administration of other anticonvulsants (Brodie et al, 1983;Jawad et al, 1984) or inhibited by cimetidine (Macphee et al, 1984;Pullar et al, 1987). Within the superfamily of cytochrome P-450, overlapping substrate specificity is common.…”

Section: Discussionmentioning

confidence: 99%

The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites.

Muñoz

Salamanca

Diaz-Obregón

et al. 1990

Brit J Clinical Pharma

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Steady state metabolite/parent drug plasma ratios were measured in 15 epileptic patients on carbamazepine (CBZ) monotherapy and in seven patients treated with CBZ and clobazam (CLB). CBZ plasma concentrations did not differ between the two groups but patients also treated with CLB exhibited higher concentrations of CBZ-10,11-epoxide (CBZ-E) and trans-10,11-dihydro-10,11-dihydroxy-CBZ (CBZ-T). Ratios between all of the metabolites of CBZ and the parent compound were higher in patients on polytherapy but the ratio between metabolites was not different. CLB comedication causes a moderate increase (about 1.5-fold) in CBZ metabolism, probably by inducing its epoxidation.

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Section: Discussionmentioning

confidence: 99%

The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites.

Muñoz

Salamanca

Diaz-Obregón

et al. 1990

Brit J Clinical Pharma

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“…Further information on CLB PK and PopPK modeling was identified from unpublished reports from the drug sponsor and from references cited in the articles obtained in the literature search. In total, over 100 English‐language articles and abstracts were reviewed; 53 published and 3 unpublished reports were used to compile the information presented here on CLB PK, use in specific patient populations, drug interactions, and PopPK analyses …”

Section: Clobazam Clinical Pharmacokineticsmentioning

confidence: 99%

“…Several reports indicated that CLB coadministration with CBZ, phenytoin, or phenobarbital, and particularly CBZ and phenytoin, induced CLB metabolism and increased N‐CLB levels . Finally, 2 studies examined the interaction between cimetidine (an inhibitor of several CYPs including CYP2C19 76 ) and CLB . Despite major differences in the doses of cimetidine administered between studies, both found that CLB exposures increased in the presence of this drug; extended duration and higher cimetidine doses significantly increased the N‐CLB maximum concentration and half‐life by 1.3‐ and 1.6‐fold, respectively …”

Section: Drug‐drug Interactionsmentioning

confidence: 99%

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Tolbert

Larsen

2018

The Journal of Clinical Pharma

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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.

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“…The 9 prior studies included a total of 82 individuals, which may incorporate 1 or 2 CYP2C19 PMs. Only 1 study 62 included an individual with a very long N-desmethylclobazam half-life, 131 hours, which is consistent with a CYP2C19 PM profile.…”

Section: Literature Reviewmentioning

confidence: 99%

Clobazam Therapeutic Drug Monitoring

Leon

Spina

Díaz

2013

Therapeutic Drug Monitoring

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Background Clobazam was recently approved for Lennox-Gastaut syndrome in the US. There is no published review article focused on clobazam therapeutic drug monitoring (TDM) in English. Methods More than two hundred clobazam articles identified by a PubMed search were carefully reviewed for information on clobazam pharmacokinetics. Clobazam is mainly metabolized by a cytochrome P450 (CYP) isoenzyme, CYP3A4, to its active metabolite, N-desmethylclobazam. Then, N-desmethylclobazam is mainly metabolized by CYP2C19 unless the individual has no CYP2C19 activity (poor metabolizer, PM). Results Using a mechanistic approach to reinterpret the published findings of steady-state TDM and single-dosing pharmacokinetic studies, four different serum clobazam concentration ratios were studied. The available limited steady-state TDM data suggest that the serum N-desmethylclobazam/clobazam ratio can be useful for clinicians, including identifying CYP2C19 PMs (ratio >25 in the absence of inhibitors). There are three possible concentration/dose (C/D) ratios. The clobazam C/D ratio has the potential to measure the contribution of CYP3A4 activity to the clearance of clobazam from the body. The N-desmethylclobazam C/D ratio does not appear to be a good measure of clobazam clearance and should be substituted with the total (clobazam+N-desmethylclobazam) C/D ratio. Conclusions Future clobazam TDM studies need to use trough concentrations after steady-state has been reached (>3 weeks in normal individuals and several months in CYP2C19 PMs). These future studies need to explore the potential of clobazam and total C/D ratios. Better studies on the relative potency of N-desmethylclobazam compared to the parent compound are needed to provide weighted total serum concentrations that correct for the possible lower N-desmethylclobazam pharmacodynamic activity. Standardization and more studies of C/D ratios from clobazam and other drugs can be helpful to move TDM forward.

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The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N‐desmethylclobazam.

Cited by 20 publications

References 17 publications

The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites.

The effect of clobazam on steady state plasma concentrations of carbamazepine and its metabolites.

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Clobazam Therapeutic Drug Monitoring

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