Journal
THERAPEUTIC DRUG MONITORING
Volume 31, Issue 5, Pages 566-574Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FTD.0b013e3181b1dd76
Keywords
clonazepam; benzodiazepine; PK/PD; DSST; LC-MS-MS
Funding
- CNPq, Brazil
- CAPES, Brazil
- FINEP Brazil
- Laboratorios Biosintetica Ltda. (Sdo Paulo, Brazil)
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This study was undertaken to model the relationship between clonazepam plasma concentrations and a central nervous system adverse effect (impairment of the psychomotor performance) following the oral administration of immediate-release tablets of clonazepam, in healthy volunteers. Such a (P)pharmacokinetic/(P)pharmacodynamic (PK/PD) study is important to interpret properly the consequences of determined levels of plasma concentrations of psychoactive therapeutic drugs reported to be involved in road-traffic accidents. Twenty-three male subjects received a single oral dose of 4 mg clonazepam. Plasma concentration, determined by online solid phase extraction coupled with high-performance liquid chromatography tandem mass spectrometry, and psychomotor performance, quantified through the Digit Symbol Substitution Test, were monitored for 72 hours. A 2-compartment open model with first order absorption and lag-time better fitted the plasma clonazepam concentrations. Clonazepam decreased the psychomotor performance by 72 +/- 3.7% (observed maximum effect), 1.5 to 4 hours (25th-75th percentile) after drug administration. A simultaneous population PK/PD model based on a sigmoid Emax model with time-dependent tolerance described well the time course of effect. Such acute tolerance could minimize the risk of accident as a result of impairment of motor skill after a single dose of clonazepam. However, an individual analysis of the data revealed a great interindividual variation in the relationship between clonazepam effect and plasma concentration, indicating that the phenomenon of acute tolerance can be predicted at a population, but not individual, level.
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