Pharmacokinetic/pharmacodynamic modeling of psychomotor impairment induced by oral clonazepam in healthy volunteers
| Autor: | Fábio Monteiro dos Santos, Ricardo Caminha, José Carlos Saraiva Gonçalves, Gabriel Parreiras Estolano da Silveira, Karla Regina da Silva Gram, François Noël, Philippe Jacqmin, Carla Teixeira Ferreira, Claúdia Silvana de Miranda Neves |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
Central Nervous System Male Pain Threshold medicine.drug_class Metabolic Clearance Rate Population Administration Oral Pharmacology Clonazepam Hypnotic Young Adult Cognition Pharmacokinetics Oral administration Reference Values Tandem Mass Spectrometry medicine Reaction Time Humans Pharmacology (medical) education PK/PD models education.field_of_study Chemistry musculoskeletal neural and ocular physiology Middle Aged Pharmacodynamics Digit symbol substitution test Psychomotor Disorders Psychomotor Performance medicine.drug |
| Zdroj: | ResearcherID |
| ISSN: | 1536-3694 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|