Athena F Zuppa1,2, Daniela J Conrado3, Nicole R Zane2, Martha A Q Curley4,5,6, Jonathan Bradfield7, Hakon Hakonarson8,9, Madeleine S Gastonguay3, Ganesh Moorthy1,2, Janice Prodell1,2, Marc R Gastonguay3. 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.
OBJECTIVES: To develop a pharmacokinetic-pharmacogenomic population model of midazolam in critically illchildren 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 UGT2B7rs62298861 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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