This work leveraged available knowledge on non-heritable and heritable factors affecting midazolam pharmacokinetic in pediatric subjects with primary respiratory failure requiring mechanical ventilation, providing the basis for a future implementation of an individual-based approach to sedation. Concentrations of midazolam, the 1′ and 4′ hydroxyl, and the 1′ and 4′ glucuronide metabolites were measured. Subjects were genotyped using the Illumina HumanOmniExpress genome-wide single nucleotide polymorphism chip. Nonlinear mixed effects modeling was performed to develop the pharmacokinetic-pharmacogenomic model. Body weight, age, hepatic and renal functions, and the UGT2B7 rs62298861 polymorphism are relevant predictors of midazolam pharmacokinetic variables. 13 PICUs across the United States and the pediatric subjects mechanically ventilated for acute respiratory failure (ARF), weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.

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