title: Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter.
abstract: Morphine shows large interindividual variability in its pharmacokinetics; however, the cause of this has not been fully addressed. The variability in morphine disposition is considered to be due to a combination of pharmacogenetic and physiological determinants related to morphine disposition. We previously reported the effect of organic cation transporter (OCT1) genotype on morphine disposition in pediatric patients. To further explore the underlying mechanisms for variability arising from relevant determinants, including OCT1, a physiologically based pharmacokinetic (PBPK) model of morphine was developed. The PBPK model predicted morphine concentration-time profiles well, in both adults and children. Almost all of the observed morphine clearances in pediatric patients fell within a twofold range of median predicted values for each OCT1 genotype in each age group. This PBPK modeling approach quantitatively demonstrates that OCT1 genotype, age-related growth, and changes in blood flow as important contributors to morphine pharmacokinetic (PK) variability.
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: C
authors.initials: C
authors.lastname: Emoto
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: T
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Simcyp Limited (a Certara company), St. Louis, Missouri, USA.
authors.forename: T N
authors.initials: TN
authors.lastname: Johnson
authors.affiliation: Simcyp Limited (a Certara company), St. Louis, Missouri, USA.
authors.forename: S
authors.initials: S
authors.lastname: Neuhoff
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sadhasivam
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000098:blood supply; D008297:Male; D008954:Models, Biological; D009020:Morphine / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D050811:Octamer Transcription Factor-1 / Q000235:genetics / Q000378:metabolism*; D000071184:Pharmacogenomic Variants; D057285:Precision Medicine
chemical_list: D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D009020:Morphine; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase