title: Age-dependent changes in sirolimus metabolite formation in patients with neurofibromatosis type 1.
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.
authors.affiliation: *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.
authors.forename: Chie
authors.initials: C
authors.lastname: Emoto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mizuno
authors.forename: Shareen
authors.initials: S
authors.lastname: Cox
authors.forename: Björn
authors.initials: B
authors.lastname: Schniedewind
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fisher
authors.forename: Brian
authors.initials: B
authors.lastname: Weiss
authors.forename: John
authors.initials: J
authors.lastname: Perentesis
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000097:blood / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009456:Neurofibromatosis 1 / Q000097:blood / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D020123:Sirolimus