title: Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children.
abstract: Various in vitro, animal, and limited human adult studies suggest a profound inhibitory effect of inflammation and disease on cytochrome P-450 3A (CYP3A)-mediated drug metabolism. Studies showing this relationship in critically ill patients are lacking, whereas clearance of many CYP3A drug substrates may be decreased, potentially leading to toxicity.
  
  
  
  To prospectively study the relationship between inflammation, organ failure, and midazolam clearance as a validated marker of CYP3A-mediated drug metabolism in critically ill children.
  
  
  
  From 83 critically ill children (median age, 5.1 mo [range, 0.02-202 mo]), midazolam plasma (n = 532), cytokine (e.g., IL-6, tumor necrosis factor-α), and C-reactive protein (CRP) levels; organ dysfunction scores (Pediatric Risk of Mortality II, Pediatric Index of Mortality 2, Pediatric Logistic Organ Dysfunction); and number of failing organs were prospectively collected. A population pharmacokinetic model to study the impact of inflammation and organ failure on midazolam pharmacokinetics was developed using NONMEM 7.3.
  
  
  
  In a two-compartmental pharmacokinetic model, body weight was the most significant covariate for clearance and volume of distribution. CRP and organ failure were significantly associated with clearance (P < 0.01), explaining both interindividual and interoccasional variability. In simulations, a CRP of 300 mg/L was associated with a 65% lower clearance compared with 10 mg/L, and three failing organs were associated with a 35% lower clearance compared with one failing organ.
  
  
  
  Inflammation and organ failure strongly reduce midazolam clearance, a surrogate marker of CYP3A-mediated drug metabolism, in critically ill children. Hence, critically ill patients receiving CYP3A substrate drugs may be at risk of increased drug levels and associated toxicity.
authors.affiliation: 1 Intensive Care.|2 Department of Pediatrics.
authors.forename: Nienke J
authors.initials: NJ
authors.lastname: Vet
authors.affiliation: 3 Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.
authors.forename: Janneke M
authors.initials: JM
authors.lastname: Brussee
authors.affiliation: 1 Intensive Care.|2 Department of Pediatrics.
authors.forename: Matthijs
authors.initials: M
authors.lastname: de Hoog
authors.affiliation: 1 Intensive Care.|4 Department of Pediatric Surgery, and.
authors.forename: Miriam G
authors.initials: MG
authors.lastname: Mooij
authors.affiliation: 5 Intensive Care, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Carin W M
authors.initials: CW
authors.lastname: Verlaat
authors.affiliation: 6 Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.
authors.forename: Isabel S
authors.initials: IS
authors.lastname: Jerchel
authors.affiliation: 7 Department of Clinical Chemistry and.
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
authors.affiliation: 8 Department of Hospital Pharmacy, Erasmus MC, Rotterdam, the Netherlands; and.
authors.forename: Birgit C P
authors.initials: BC
authors.lastname: Koch
authors.affiliation: 1 Intensive Care.|4 Department of Pediatric Surgery, and.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: 3 Division of Pharmacology, Leiden Academic Center for Drug Research, Leiden University, Leiden, the Netherlands.|9 Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
authors.affiliation: 1 Intensive Care.|4 Department of Pediatric Surgery, and.
authors.forename: Saskia N
authors.initials: SN
authors.lastname: de Wildt
mesh_terms: D000293:Adolescent; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation / Q000378:metabolism*; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D009102:Multiple Organ Failure / Q000378:metabolism*; D011446:Prospective Studies
chemical_list: D018686:Anesthetics, Intravenous; D008874:Midazolam
keywords: critical illness; inflammation; midazolam; pediatrics; pharmacokinetics