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The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic

Bianca D van Groen1, Elke H J Krekels2, Miriam G Mooij3

  • 1Intensive Care and Pediatric Surgery, Erasmus Medical Center - Sophia Children's Hospital, Rotterdam, The Netherlands.

Clinical Pharmacology and Therapeutics
|May 14, 2020
PubMed

Insights

Oral midazolam bioavailability in children up to one year old varies widely, impacting drug metabolite exposure. This variability suggests unpredictable systemic exposure for other CYP3A-substrate drugs, increasing risks of toxicity or treatment failure.

Area of Science:

  • Pharmacokinetics and Drug Metabolism
  • Pediatric Pharmacology
  • Drug Bioavailability Studies

Background:

  • Midazolam, metabolized by cytochrome P450 (CYP) 3A4/5, is orally administered to children.
  • Limited data exists on oral midazolam bioavailability and its metabolite disposition in neonates and infants.
  • Understanding pediatric drug metabolism is crucial for safe and effective therapeutic interventions.

Purpose of the Study:

  • To determine oral midazolam bioavailability in critically ill children from term neonates up to one year of age.
  • To investigate the disposition of major midazolam metabolites, 1-OH-midazolam (OHM) and 1-OH-midazolam-glucuronide (OHMG).
  • To fill knowledge gaps regarding oral drug pharmacokinetics in the pediatric population.

Main Methods:

  • A pediatric population pharmacokinetic study using a [14C]midazolam microtracer.
  • Forty-six critically ill children received a single oral [14C]midazolam microtracer dose.
  • One-compartment model analysis incorporating bodyweight for clearance and volume of distribution.

Main Results:

  • Typical oral midazolam bioavailability was 66% (range 25-85%), varying significantly with age.
  • Exposures of OHM and OHMG were highest in the youngest infants and decreased with postnatal age.
  • Oral bioavailability was lower than in preterm neonates but higher than in older children and adults.

Conclusions:

  • Oral midazolam bioavailability in children up to one year is highly variable, reflecting developmental changes in CYP3A activity.
  • The unpredictable bioavailability poses risks for therapy failure or toxicity with oral midazolam and other CYP3A substrates.
  • Further research is needed to optimize dosing strategies for CYP3A-metabolized drugs in pediatric populations.

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