title: Pharmacokinetic/pharmacodynamic modeling of psychomotor impairment induced by oral clonazepam in healthy volunteers.
abstract: 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 on-line 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.
authors.affiliation: Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Rio de Janeiro, Brazil.
authors.forename: Fábio Monteiro
authors.initials: FM
authors.lastname: dos Santos
authors.forename: José Carlos Saraiva
authors.initials: JC
authors.lastname: Gonçalves
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caminha
authors.forename: Gabriel Estolano
authors.initials: GE
authors.lastname: da Silveira
authors.forename: Claúdia Silvana de Miranda
authors.initials: CS
authors.lastname: Neves
authors.forename: Karla Regina da Silva
authors.initials: KR
authors.lastname: Gram
authors.forename: Carla Teixeira
authors.initials: CT
authors.lastname: Ferreira
authors.forename: Philippe
authors.initials: P
authors.lastname: Jacqmin
authors.forename: François
authors.initials: F
authors.lastname: Noël
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002490:Central Nervous System / Q000187:drug effects* / Q000503:physiopathology; D002998:Clonazepam / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D017288:Pain Threshold; D011596:Psychomotor Disorders / Q000139:chemically induced* / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects*; D011930:Reaction Time; D012016:Reference Values; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D002998:Clonazepam