Athena F Zuppa1,2, Giselle R Benitez3, Nicole R Zane2, Martha A Q Curley4,5,6, Jonathan Bradfield7, Hakon Hakonarson8,9, Madeleine S Gastonguay10, Ganesh Moorthy1,2, Janice Prodell1,2, Marc R Gastonguay10. 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. Long Island University Brooklyn Campus, Brooklyn, NY. 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. 10. Metrum Research Group, Tariffville, CT.
Abstract
OBJECTIVE: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure. DESIGN: Prospective pharmacokinetic-pharmacogenomic observational study. SETTING: Thirteen PICUs across the United States. PATIENTS: Pediatric subjects (n = 66) 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 morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. 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. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified. CONCLUSIONS: The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.
OBJECTIVE: To develop a pharmacokinetic-pharmacogenomic population model of morphine in critically ill children with acute respiratory failure. DESIGN: Prospective pharmacokinetic-pharmacogenomic observational study. SETTING: Thirteen PICUs across the United States. PATIENTS: Pediatric subjects (n = 66) 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 morphine, the two main metabolites, morphine-3-glucuronide and morphine-6-glucuronide, were quantified by high-performance liquid chromatography tandem mass spectrometry/mass spectroscopy. 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. A two-compartment model with linear elimination and two individual compartments for metabolites best describe morphine disposition in this population. Our analysis demonstrates that body weight and postmenstrual age are relevant predictors of pharmacokinetic parameters of morphine and its metabolites. Furthermore, our research shows that a duration of mechanical ventilation greater than or equal to 10 days reduces metabolite formation and elimination upwards of 30%. However, due to the small sample size and relative heterogeneity of the population, no heritable factors associated with uridine diphosphate glucuronyl transferase 2B7 metabolism of morphine were identified. CONCLUSIONS: The results provide a better understanding of the disposition of morphine and its metabolites in critically ill children with acute respiratory failure requiring mechanical ventilation due to nonheritable factors. It also provides the groundwork for developing additional studies to investigate the role of heritable factors.
Authors: Su H Chu; Emily S Wan; Michael H Cho; Sergey Goryachev; Vivian Gainer; James Linneman; Erica J Scotty; Scott J Hebbring; Shawn Murphy; Jessica Lasky-Su; Scott T Weiss; Jordan W Smoller; Elizabeth Karlson Journal: Sci Rep Date: 2021-10-07 Impact factor: 4.379
Authors: Uri Pollak; Yael Feinstein; Candace N Mannarino; Mary E McBride; Malaika Mendonca; Eitan Keizman; David Mishaly; Grace van Leeuwen; Peter P Roeleveld; Lena Koers; Darren Klugman Journal: Front Pediatr Date: 2022-09-16 Impact factor: 3.569