A drug’s oral bioavailability is the fraction of an oral dose that reaches the systemic circulation. In a 2018 midazolam modeling study, that fraction was estimated to be substantially higher in preterm neonates than the adult value discussed by the authors. Developmental changes in metabolism were central to the explanation.
Brussee and colleagues analyzed midazolam and 1-hydroxymidazolam concentration data from 37 preterm neonates with gestational ages of 26–34 weeks. Administration was oral, intravenous, or both. A physiological population pharmacokinetic model separated estimated intestinal and hepatic handling of the drug.
The model-derived total oral bioavailability was 92.1%, with a reported range of 67–95%. The adult comparison discussed in the paper was approximately 30%. Low extraction in both the gut wall and liver allowed a large fraction of the oral dose to escape first-pass metabolism.
The estimated intrinsic gut-wall clearance had a relative standard error of 178%. The authors explicitly interpreted the available data as providing a poorly precise estimate of that parameter. Feeding times were unavailable, some physiological quantities required assumptions, and organ blood flows were scaled from other neonatal data.
For an expert assessing a neonatal medication timeline, route, gestational age, sampling times, and the population supporting a pharmacokinetic estimate all matter. Applying an adult oral fraction could distort the interpretation of an administered amount or expected concentration. The study supports age-specific interpretation while leaving uncertainty around individual estimates and the exact allocation of metabolism between organs.