Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants. (4th February 2015)

• Record Type: Journal Article
• Authors: Emoto, C; Fukuda, T; Johnson, TN; Adams, DM; Vinks, AA
• Is Part Of: CPT: pharmacometrics & systems pharmacology. Volume 4:Number 2(2015:Feb.)
• Page Start: 1
• Page End: 8
• Publication Date: 2015-02-04
• Subjects: Pharmacokinetics -- Periodicals; Pharmacology -- Periodicals; Pharmacokinetics; Periodicals; 615.05
• DOI: 10.1002/psp4.17
• Languages: English
• ISSNs: 2163-8306

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>This study describes the maturation of sirolimus clearance in a cohort of very young pediatric patients with vascular anomalies. The relationship between allometrically scaled <italic>in vivo</italic> clearance and age was described by the E_max model in patients aged 1 month to 2 years. Consistent with the observed increase, <italic>in vitro</italic> 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 <italic>in vivo</italic> 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.</p> </abstract>