Semi‐mechanistic autoinduction model of midazolam in critically ill patients: population pharmacokinetic analysis. (12th May 2016)

• Record Type: Journal Article
• Authors: Aoyama, T.; Hirata, K.; Yamamoto, Y.; Yokota, H.; Hayashi, H.; Aoyama, Y.; Matsumoto, Y.
• Is Part Of: Journal of clinical pharmacy and therapeutics. Volume 41:Number 4(2016:Aug.)
• Page Start: 392
• Page End: 398
• Publication Date: 2016-05-12
• Subjects: autoinduction -- critically ill patients -- midazolam -- NONMEM -- population pharmacokinetics; Clinical pharmacology -- Periodicals; Chemotherapy -- Periodicals; 615
• DOI: 10.1111/jcpt.12395
• Languages: English
• ISSNs: 0269-4727

Abstract

Summary: What is known and 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. Results and discussion: 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. What is new and conclusion: 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. Abstract : A population pharmacokinetic model of midazolam in critically ill patients incorporating semi‐mechanistic enzyme turnover was developed. Autoinduction of clearance and total bilirubin were significant predictors of the clearance of midazolam in this population. Stepwise dosage adjustment using the model may be useful for establishing a midazolam dosage regimen in critically ill patients.