Mojca Kerec Kos1, Mirjana Miksić2, Marija Jovanović3, Robert Roškar4, Štefan Grosek5, Iztok Grabnar4. 1. Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia. Electronic address: kerecm@ffa.uni-lj.si. 2. Division of Paediatrics, University Medical Centre Maribor, Ljubljanska ulica 5, Maribor 2000, Slovenia; Division of Gynaecology and Perinatology, Department of Perinatology, University Medical Centre Maribor, Ljubljanska ulica 5, Maribor 2000, Slovenia. 3. Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade 11221, Serbia. 4. Faculty of Pharmacy, University of Ljubljana, Askerceva cesta 7, Ljubljana 1000, Slovenia. 5. Division of Surgery, Department of Paediatric Surgery and Intensive Therapy, University Medical Centre Ljubljana, Bohoriceva ulica 20, Ljubljana 1525, Slovenia; Department of Perinatology, Divison of Gynecology and Obstetrics, University Medical Centre Ljubljana, Šlajmerjeva 3, Ljubljana 1000, Slovenia; Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana 1000, Slovenia.
Abstract
PURPOSE: The aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. METHODS: In the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. RESULTS: The final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. CONCLUSIONS: The developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.
PURPOSE: The aim of the present study was to develop a population pharmacokinetic model of midazolam, and to evaluate the influence of maturation process and other variability factors in critically ill children with severe acute bronchiolitis, who received a long-term intravenous infusion of midazolam. METHODS: In the study were included 49 critically ill children of both genders (from 0 to 130 weeks of age) with severe acute bronchiolitis hospitalised in intensive care units. Nonlinear mixed effects modelling approach was applied for data analyses and simulations. RESULTS: The final model is a two-compartment model that includes the effects of body weight using allometric scaling with fixed exponents and maturation of clearance. For a typical subject, scaled to the adult body weight of 70 kg, population pharmacokinetic values were estimated at 8.52 L/h for clearance (when maturation function was 1), 25.5 L/h for intercompartmental clearance, and 5.71 L and 39.8 L for the volume of the central and peripheral compartment, respectively. Based on the final model, maturation reaches 50% of the adult clearance in 45.9 weeks of postmenstrual age. The influence of gender, ABCB1 genotype and biochemical parameters on midazolam clearance was not detected. Results of simulations indicate the need for reduced dosing in certain groups of patients in order to maintain plasma concentrations of midazolam within recommended values. CONCLUSIONS: The developed population pharmacokinetic model can contribute to the dosing optimisation of midazolam, especially in critically ill children as it includes the influence of size and maturation of clearance, which are important parameters for achieving the desired plasma concentrations of midazolam.