Pharmacokinetics of a Single Oral Dose of Clobazam in Patients with Liver Disease

Monjanel-Mouterde, Suzanne; Antoni, M.; Bun, H.; Botta‐Frindlund, Danielle; Gauthier, A.; Durand, Alain; Cano, Jean Paul

doi:10.1111/j.1600-0773.1994.tb01371.x

Cited by 16 publications

(22 citation statements)

References 20 publications

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“…The C max of CLB was decreased by approximately 31% in participants with chronic liver disease; however, the mean oral clearance of CLB was approximately the same between those with liver disease and healthy subjects. Furthermore, there were no significant differences in the maximum concentrations of N‐CLB between healthy subjects and patients with liver disease; even after simulation of single doses to steady state, plasma concentrations were the same for all subjects . The elimination half‐life was 2 times longer in participants with liver disease compared with healthy controls .…”

Section: Specific Populationsmentioning

confidence: 89%

“…Further information on CLB PK and PopPK modeling was identified from unpublished reports from the drug sponsor and from references cited in the articles obtained in the literature search. In total, over 100 English‐language articles and abstracts were reviewed; 53 published and 3 unpublished reports were used to compile the information presented here on CLB PK, use in specific patient populations, drug interactions, and PopPK analyses …”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

“…The PK of CLB was determined after a single oral dose of 20 mg CLB in participants with liver disease (hepatitis and cirrhosis) and in healthy controls . The C max of CLB was decreased by approximately 31% in participants with chronic liver disease; however, the mean oral clearance of CLB was approximately the same between those with liver disease and healthy subjects.…”

Section: Specific Populationsmentioning

confidence: 99%

“…Furthermore, there were no significant differences in the maximum concentrations of N‐CLB between healthy subjects and patients with liver disease; even after simulation of single doses to steady state, plasma concentrations were the same for all subjects . The elimination half‐life was 2 times longer in participants with liver disease compared with healthy controls . A PopPK analysis investigating CLB use in patients with hepatic impairment was also developed and is described in a later section (see also Population PK Analyses, Drug‐Drug Interaction Potential).…”

Section: Specific Populationsmentioning

confidence: 99%

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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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Section: Specific Populationsmentioning

confidence: 89%

Section: Clobazam Clinical Pharmacokineticsmentioning

confidence: 99%

Section: Specific Populationsmentioning

confidence: 99%

Section: Specific Populationsmentioning

confidence: 99%

See 2 more Smart Citations

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Tolbert

Larsen

2018

The Journal of Clinical Pharma

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“…No data on co-medications in patients was provided, but the results in patients were probably contaminated by inducers. In a single-dose study, Monjanel-Mouterde et al 60 demonstrated differences in clobazam half-lives between volunteers and patients with hepatic impairment, but N-desmethylclobazam was not studied.…”

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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An integrative population pharmacokinetics approach to the characterization of the effect of hepatic impairment on clobazam pharmacokinetics

Tolbert

Bekersky

Chu³

et al. 2015

The Journal of Clinical Pharma

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An integrative population pharmacokinetics (PPK)-based approach was used to characterize the effect of hepatic impairment on clobazam PK and its major metabolite in systemic circulation, N-desmethylclobazam (N-CLB). At therapeutic clobazam dosages, N-CLB plasma concentrations are 3-5 times greater than the parent compound. PK data from clinical trials in patients with Lennox-Gastaut syndrome (LGS; OV-1002 and OV-1012), healthy participants (OV-1016), and participants with and without renal impairment (OV-1032), as well as those from a publication describing the effects of hepatic impairment on clobazam PK, were merged to create the PPK model. Individual patient clobazam PK parameters from the publication were used to generate patient plasma-concentration data. Clobazam PK was linear and the formation of N-CLB was elimination-rate limited. Hepatic impairment did not affect the total apparent clearance of clobazam but may affect the PK of N-CLB. Because the formation of N-CLB is elimination-rate limited and the total apparent clearance of clobazam is unaffected by hepatic impairment, the PPK model suggests that patients with LGS and hepatic impairment may not require clobazam dosage modification.

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Pharmacokinetics of a Single Oral Dose of Clobazam in Patients with Liver Disease

Cited by 16 publications

References 20 publications

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

Clobazam Therapeutic Drug Monitoring

An integrative population pharmacokinetics approach to the characterization of the effect of hepatic impairment on clobazam pharmacokinetics

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