Critical illness is a major determinant of midazolam clearance in children aged 1 month to 17 years.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Pediatric Surgery and Intensive Care, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands.
Ibrahim
I
Ince
Saskia N
SN
de Wildt
Mariska Y M
MY
Peeters
Daryl J
DJ
Murry
Dick
D
Tibboel
Meindert
M
Danhof
Catherijne A J
CA
Knibbe
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007362:Intensive Care Units; D008874:Midazolam / Q000493:pharmacokinetics* / Q000627:therapeutic use
C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase; D008874:Midazolam