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In children, a large variability in pharmacokinetics of midazolam, a cytochrome P450 3A4/5 (CYP3A4/5) enzyme substrate, has been described, which cannot be explained by age-related changes alone. In this study, these age-related changes are studied in relation to other covariates to explain the variability in the pharmacokinetics of midazolam in children.Population pharmacokinetic modeling was performed using a joint dataset of 3 studies conducted previously: study 1: pediatric intensive care patients requiring sedation in the intensive care unit; study 2: pediatric oncology patients undergoing an invasive procedure; study 3: otherwise healthy infants admitted for postoperative monitoring after elective major craniofacial surgery. Midazolam, 1-hydroxymidazolam, and 1-hydroxymidazolam glucuronide concentrations were considered to determine the pharmacokinetics of midazolam and metabolites using NONMEM 6.2. SimCYP pediatric simulator was used for simulation.Fifty-four children aged between 1 month and 17 years who received intravenous midazolam (bolus and/or continuous infusion) for sedation were included in this study. A reduction of 93% for CYP3A4/5 (midazolam to 1-hydroxymidazolam) and 86% for uridine diphosphate glucuronosyltransferase (1-hydroxymidazolam to 1-hydroxymidazolam glucuronide) mediated clearance was found in pediatric intensive care patients compared with the other 2 patient groups. We did not find a significant influence of age or bodyweight on CYP3A4/5-mediated total clearance. For uridine diphosphate glucuronosyltransferase–mediated clearance, bodyweight explained 41.5% of the variability.From infancy to adolescence, critical illness seems to be a major determinant of midazolam clearance, which may result from reduced CYP3A4/5 activity due to inflammation. This may have important implications for dosing of midazolam and other CYP3A drug substrates in critically ill children.