DDMODEL00000249: Midazolam PK in critically ill pediatric patients

  public model
Short description:
Midazolam PK in critically ill pediatric patients. Inflammation (quantified as CRP concentrations) and number of organs failing are most important covariates.
Original code
  • Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children.
  • Vet NJ, Brussee JM, de Hoog M, Mooij MG, Verlaat CW, Jerchel IS, van Schaik RH, Koch BC, Tibboel D, Knibbe CA, de Wildt SN
  • American journal of respiratory and critical care medicine, 7/2016, Volume 194, Issue 1, pages: 58-66
  • 2 Department of Pediatrics.
  • 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-?), 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?
Catherijne Knibbe
Context of model development: Dose & Schedule Selection and Label Recommendation;
Model compliance with original publication: Yes;
Model implementation requiring submitter’s additional knowledge: No;
Modelling context description: Midazolam PK in critically ill pediatric patients, using inflammation (quantified as CRP concentrations) and number of organs failing are most important covariates;
Modelling task in scope: estimation;
Nature of research: Clinical research & Therapeutic use;
Therapeutic/disease area: Metabolism;
Annotations are correct.
This model is not certified.
  • Model owner: Catherijne Knibbe
  • Submitted: Oct 9, 2017 1:22:09 PM
  • Last Modified: Oct 9, 2017 1:22:09 PM
  • Version: 10 public model Download this version
    • Submitted on: Oct 9, 2017 1:22:09 PM
    • Submitted by: Catherijne Knibbe
    • With comment: Edited model metadata online.