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

Abstract

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.

Figure 1

Flowchart of patient recruitment. ECMO, extra corporeal membrane oxygenation; IV, intravenous; PICU, pediatric intensive care unit; PMA, postmenstrual age.

Figure 2

Oral bioavailability of midazolam and its variability vs. bodyweight. Bodyweight did not explain the variability in oral bioavailability.

Figure 3

Area under the curve from time zero to the last sampling time point (AUC_0–tlast) after administration of an oral [¹⁴C]midazolam microtracer (20.3 (14.1–23.6) ng/kg; 58 (40–67) Bq/kg) of (a) midazolam, (b) 1‐OH‐midazolam, and (c) 1‐OH‐midazolam‐glucuronide vs. postnatal age (log scale). ρ, Spearman’s rank correlation; OHM, 1‐OH‐midazolam (n = 38); OHMG, 1‐OH‐midazolam‐glucuronide (n = 43); P, P value where P < 0.05 is statistically significant.