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Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth

C Emoto1, T Fukuda1, T N Johnson2

  • 1Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center Cincinnati, Ohio, USA ; Department of Pediatrics, University of Cincinnati College of Medicine Cincinnati, Ohio, USA.

CPT: Pharmacometrics & Systems Pharmacology
|July 31, 2015
PubMed

Insights

Sirolimus clearance matures in young children, with clearance stabilizing after age two. Physiologically based pharmacokinetic modeling accurately predicts sirolimus metabolism and clearance in pediatric patients.

Area of Science:

  • Pharmacology
  • Pediatric Medicine
  • Drug Metabolism

Background:

  • Sirolimus is crucial for treating vascular anomalies in pediatric patients.
  • Understanding sirolimus pharmacokinetics in children is vital for safe and effective dosing.
  • Pediatric drug metabolism undergoes significant developmental changes.

Purpose of the Study:

  • To characterize the maturation of sirolimus clearance in very young pediatric patients.
  • To evaluate the utility of physiologically based pharmacokinetic (PBPK) modeling for predicting sirolimus clearance.
  • To investigate the age-dependent changes in sirolimus metabolic activity.

Main Methods:

  • Collected pharmacokinetic data from pediatric patients with vascular anomalies.
  • Utilized the Emax model to describe age-related changes in allometrically scaled sirolimus clearance.
  • Employed in vitro studies with pediatric liver microsomes to assess intrinsic clearance.
  • Developed and validated a PBPK model incorporating CYP450 enzyme maturation (CYP3A4/5/7, CYP2C8).

Main Results:

  • Sirolimus clearance showed significant age-dependent maturation in children from 1 month to 2 years.
  • Intrinsic clearance in pediatric liver microsomes mirrored the in vivo age-related increase.
  • Sirolimus clearance stabilized in children older than 2 years.
  • PBPK model simulations closely matched observed in vivo clearance and pharmacokinetic profiles.

Conclusions:

  • Sirolimus clearance maturation follows a predictable trajectory in early childhood.
  • PBPK modeling is a valuable tool for predicting developmental changes in sirolimus pharmacokinetics.
  • This approach can aid in optimizing sirolimus dosing strategies for pediatric populations.

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