title: Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants.
abstract: This study describes the maturation of sirolimus clearance in a cohort of very young pediatric patients with vascular anomalies. The relationship between allometrically scaled in vivo clearance and age was described by the Emax model in patients aged 1 month to 2 years. Consistent with the observed increase, in vitro intrinsic clearance of sirolimus using pediatric liver microsomes showed a similar age-dependent increase. In children older than 2 years, allometrically scaled sirolimus clearance did not show further maturation. Simulated clearance estimates with a sirolimus physiologically based pharmacokinetic model that included CYP3A4/5/7 and CYP2C8 maturation profiles were in close agreement with observed in vivo clearance values. In addition, physiologically based pharmacokinetic model-simulated sirolimus pharmacokinetic profiles predicted the actual observations well. These results demonstrate the utility of a physiologically based pharmacokinetic modeling approach for the prediction of the developmental trajectory of sirolimus metabolic activity and its effects on total body clearance in neonates and infants.
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, USA ; Department of Pediatrics, University of Cincinnati College of Medicine 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, University of Cincinnati College of Medicine Cincinnati, Ohio, USA.
authors.forename: T
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Simcyp Limited, Blades Enterprise Centre John Street, Sheffield, UK.
authors.forename: T N
authors.initials: TN
authors.lastname: Johnson
authors.affiliation: Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, Ohio, USA ; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Adams
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, USA ; Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, Ohio, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Vinks