What question did this study set out to answer?

To develop a physiological based pharmacokinetic (PBPK) model for midazolam in neonates undergoing therapeutic hypothermia for perinatal asphyxia.

May 15, 2026

Neonatal PBPK model of midazolam and its metabolites for perinatal asphyxia and therapeutic hypothermia

Puntos clave

To develop a physiological based pharmacokinetic (PBPK) model for midazolam in neonates undergoing therapeutic hypothermia for perinatal asphyxia.
Established PBPK model starting with healthy adults and extrapolated to pediatric and neonatal populations.
Incorporated physiological and metabolic changes related to perinatal asphyxia and therapeutic hypothermia.
Verified model performance using clinical data for midazolam and its metabolites.
Model predictive performance for midazolam and 1'-hydroxymidazolam showed AFE values between 0.87 and 1.22.
Neonatal PA/TH PBPK model captured midazolam pharmacokinetics with 71% of observations within the 10th-90th percentiles.
Incorporating PA/TH physiology improved model performance by 6%-43% for midazolam based on the compound.

Resumen

BACKGROUND AND PURPOSE: Therapeutic hypothermia (TH) decreases morbidity and mortality in neonates with perinatal asphyxia (PA) and moderate-to-severe hypoxic-ischaemic encephalopathy. Midazolam is an antiepileptic and substrate of CYP3A4. Drug metabolism during PA/TH remains partially characterized, and disentangling effects of PA and TH is difficult, making precision dosing challenging. The I-PREDICT project aims to develop a framework for drug disposition in PA/TH neonates, using physiologically based pharmacokinetic (PBPK) modelling. The predictive performance of the model was explored for midazolam and its active metabolites, 1'-hydroxymidazolam and 1'-hydroxymidazolam-O-glucuronide, in neonates with PA/TH. EXPERIMENTAL APPROACH: The model was established stepwise, starting with healthy adults, and extrapolated to paediatric (1 month-18 years) and neonatal (0-27 days, non-asphyxiated) populations. Finally, PA/TH-related physiological and metabolic changes were incorporated. For each population, performance was verified using clinical data. KEY RESULTS: Model predictive performance for midazolam and 1'-hydroxymidazolam was acceptable in adults and children, with AFE and AAFE values ranging from 0.87 to 1.22 and 1.15 to 1.23, respectively. The neonatal PA/TH PBPK model captured midazolam pharmacokinetics, with 71% of the observations within the 10th-90th percentiles and 46% within the 25th-75th percentiles of the prediction. Incorporating PA/TH physiology improved the neonatal PA/TH model by 6%-43% (within the 10th-90th percentiles), depending on the compound. CONCLUSIONS AND IMPLICATIONS: This PA/TH-adjusted neonatal PBPK model may support future midazolam dose optimization through mechanistic understanding and provides a framework for other drugs in neonates with PA/TH. Future knowledge on the impact of TH on protein binding and renal clearance of 1'-hydroxymidazolam-O-glucuronide would further improve the model.

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