Chie Emoto1, Tsuyoshi Fukuda, Tomoyuki Mizuno, Shareen Cox, Björn Schniedewind, Uwe Christians, Brigitte C Widemann, Michael J Fisher, Brian Weiss, John Perentesis, Alexander A Vinks. 1. *Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center; †Department of Pediatrics, College of Medicine, University of Cincinnati, OH; ‡iC42 Integrated Solutions in Clinical Research and Development, University of Colorado, Aurora; §Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; ¶Division of Oncology, The Children's Hospital of Philadelphia; ‖Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia; **Division of Oncology, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center; and ††Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, OH.
Abstract
BACKGROUND: Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism. METHODS: Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC-UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation. RESULTS: Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults. CONCLUSIONS: This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of age-appropriate dosing algorithms for sirolimus in infants and children.
BACKGROUND:Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism. METHODS: Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC-UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation. RESULTS: Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults. CONCLUSIONS: This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of age-appropriate dosing algorithms for sirolimus in infants and children.
Authors: Joshua C Euteneuer; Suyog Kamatkar; Tsuyoshi Fukuda; Alexander A Vinks; Henry T Akinbi Journal: J Clin Pharmacol Date: 2018-09-11 Impact factor: 3.126
Authors: Joshua C Euteneuer; Tomoyuki Mizuno; Tsuyoshi Fukuda; Junfang Zhao; Kenneth D R Setchell; Louis J Muglia; Alexander A Vinks Journal: Ther Drug Monit Date: 2020-10 Impact factor: 3.118