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Crit Care Med. 2019 Apr;47(4):e301-e309. doi: 10.1097/CCM.0000000000003638.

Midazolam Dose Optimization in Critically Ill Pediatric Patients With Acute Respiratory Failure: A Population Pharmacokinetic-Pharmacogenomic Study.

Author information

1
Department of Pediatric Anesthesia and Critical Care Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.
2
Children's Hospital of Philadelphia, Center for Clinical Pharmacology, Philadelphia, PA.
3
Metrum Research Group, Tariffville, CT.
4
Family and Community Heath, University of Pennsylvania School of Nursing, Philadelphia, PA.
5
Anesthesia and Critical Care Medicine, Perelman School of Medicine, Philadelphia, PA.
6
Research Institute, Children's Hospital of Philadelphia, PA.
7
Quantinuum Research LLC, San Diego CA.
8
Children's Hospital of Philadelphia, Center for Applied Genomics, Philadelphia, PA.
9
Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine, Philadelphia, PA.

Abstract

OBJECTIVES:

To develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically ill children with primary respiratory failure.

DESIGN:

Prospective pharmacokinetic-pharmacogenomic observational study.

SETTING:

Thirteen PICUs across the United States.

PATIENTS:

Pediatric subjects mechanically ventilated for acute respiratory failure, weight greater than or equal to 7 kg, receiving morphine and/or midazolam continuous infusions.

INTERVENTIONS:

Serial blood sampling for drug quantification and a single blood collection for genomic evaluation.

MEASUREMENTS AND MAIN RESULTS:

Concentrations of midazolam, the 1' (1`-hydroxymidazolam metabolite) and 4' (4`-hydroxymidazolam metabolite) 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. The estimated midazolam clearance was 0.61 L/min/70kg. Time to reach 50% complete mature midazolam and 1`-hydroxymidazolam metabolite/4`-hydroxymidazolam metabolite clearances was 1.0 and 0.97 years postmenstrual age. The final model suggested a decrease in midazolam clearance with increase in alanine transaminase and a lower clearance of the glucuronide metabolites with a renal dysfunction. In the pharmacogenomic analysis, rs62298861 and rs28365062 in the UGT2B7 gene were in high linkage disequilibrium. Minor alleles were associated with a higher 1`-hydroxymidazolam metabolite clearance in Caucasians. In the pharmacokinetic-pharmacogenomic model, clearance was expected to increase by 10% in heterozygous and 20% in homozygous for the minor allele with respect to homozygous for the major allele.

CONCLUSIONS:

This work leveraged available knowledge on nonheritable 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.

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