title: Semi-mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis.
abstract: OBJECTIVE
  Midazolam (MDZ) is commonly used for sedating critically ill patients. The daily dose required for adequate sedation increases in increments over 100 h after administration. The objectives of this study were to characterize the MDZ pharmacokinetics in critically ill patients and to describe the phenomenon of increasing daily dose by means of population pharmacokinetic analysis.
  
  
  METHODS
  Data were obtained from 30 patients treated in an intensive care unit. The patients received MDZ intravenously as a combination of bolus and continuous infusion. Serum MDZ concentration was assayed by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using the NONMEM software package. The alteration of clearance unexplained by demographic factors and clinical laboratory data was described as an autoinduction of MDZ clearance using a semi-mechanistic pharmacokinetic-enzyme turnover model.
  
  
  CONCLUSIONS
  The final population pharmacokinetic model was a one-compartment model estimated by incorporating a semi-mechanistic pharmacokinetic-enzyme turnover model for clearance, taking autoinduction into account. A significant covariate for MDZ clearance was total bilirubin. An increase in total bilirubin indicated a reduction in MDZ clearance. From simulation using the population pharmacokinetic parameters obtained in this study, MDZ clearance increased 2·3 times compared with pre-induced clearance 100 h after the start of 12·5 mg/h continuous infusion.
  
  
  CONCLUSIONS
  Autoinduction and total bilirubin were significant predictors of the clearance of MDZ in this population. Step-by-step dosage adjustment using this population pharmacokinetic model may be useful for establishing a MDZ dosage regimen in critically ill patients.
authors.affiliation: Laboratory of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Department of Pharmacy, Fureai Higashitotsuka Hospital, Yokohama, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Department of Emergency and Critical Care Medicine, Nippon Medical School Hospital, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Emergency and Critical Care Medicine, Nippon Medical School Hospital, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yokota
authors.affiliation: Laboratory of Pharmacotherapy, School of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Laboratory of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, Japan.|Second Department of Anesthesiology, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Aoyama
authors.affiliation: Laboratory of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsumoto
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D001663:Bilirubin / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007362:Intensive Care Units; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D055815:Young Adult
chemical_list: D006993:Hypnotics and Sedatives; D008874:Midazolam; D001663:Bilirubin
keywords: NONMEM; autoinduction; critically ill patients; midazolam; population pharmacokinetics