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The Oral Bioavailability and Metabolism of Midazolam in Stable Critically Ill Children: A Pharmacokinetic Microtracing Study
Author(s) -
Groen Bianca D.,
Krekels Elke H. J.,
Mooij Miriam G.,
Duijn Esther,
Vaes Wouter H. J.,
Windhorst Albert D.,
Rosmalen Joost,
Hartman Stan J. F.,
Hendrikse N. Harry,
Koch Birgit C. P.,
Allegaert Karel,
Tibboel Dick,
Knibbe Catherijne A. J.,
Wildt Saskia N.
Publication year - 2021
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1890
Subject(s) - bioavailability , midazolam , cyp3a , pharmacokinetics , medicine , pharmacology , population , first pass effect , oral administration , volume of distribution , dosing , physiology , anesthesia , cytochrome p450 , metabolism , environmental health , sedation
Midazolam is metabolized by the developmentally regulated intestinal and hepatic drug‐metabolizing enzyme cytochrome P450 (CYP) 3A4/5. It is frequently administered orally to children, yet knowledge is lacking on the oral bioavailability in term neonates up until 1 year of age. Furthermore, the dispositions of the major metabolites 1‐OH‐midazolam (OHM) and 1‐OH‐midazolam‐glucuronide (OHMG) after oral administration are largely unknown for the entire pediatric age span. We aimed to fill these knowledge gaps with a pediatric [ 14 C]midazolam microtracer population pharmacokinetic study. Forty‐six stable, critically ill children (median age 9.8 (range 0.3–276.4) weeks) received a single oral [ 14 C]midazolam microtracer (58 (40–67) Bq/kg) when they received a therapeutic continuous intravenous midazolam infusion and had an arterial line in place enabling blood sampling. For midazolam, in a one‐compartment model, bodyweight was a significant predictor for clearance (0.98 L/hour) and volume of distribution (8.7 L) (values for a typical individual of 5 kg). The typical oral bioavailability in the population was 66% (range 25–85%). The exposures of OHM and OHMG were highest for the youngest age groups and significantly decreased with postnatal age. The oral bioavailability of midazolam, largely reflective of intestinal and hepatic CYP3A activity, was on average lower than the reported 49–92% for preterm neonates, and higher than the reported 21% for children> 1 year of age and 30% for adults. As midazolam oral bioavailability varied widely, systemic exposure of other CYP3A–substrate drugs after oral dosing in this population may also be unpredictable, with risk of therapy failure or toxicity.