T Aoyama1, K Hirata2, Y Yamamoto3, H Yokota3, H Hayashi4, Y Aoyama1,5, Y Matsumoto1. 1. Laboratory of Clinical Pharmacokinetics, School of Pharmacy, Nihon University, Chiba, Japan. 2. Department of Pharmacy, Fureai Higashitotsuka Hospital, Yokohama, Japan. 3. Department of Emergency and Critical Care Medicine, Nippon Medical School Hospital, Tokyo, Japan. 4. Laboratory of Pharmacotherapy, School of Pharmacy, Nihon University, Chiba, Japan. 5. Second Department of Anesthesiology, Toho University School of Medicine, Tokyo, Japan.
Abstract
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.
WHAT IS KNOWN AND OBJECTIVE:Midazolam (MDZ) is commonly used for sedating critically illpatients. 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 illpatients 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 illpatients.