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Developmental changes in morphine clearance across the entire paediatric age range are best described by a

Chenguang Wang1, Senthilkumar Sadhavisvam, Elke H J Krekels

  • 1LACDR, Division of Pharmacology, Leiden University, Leiden, The Netherlands.

Clinical Drug Investigation
|June 12, 2013
PubMed

Insights

This study developed a bodyweight-based exponential (BDE) model to accurately predict morphine clearance in children. The BDE model effectively scales morphine and glucuronidation clearance across all pediatric age ranges.

Area of Science:

  • Pharmacokinetics
  • Pediatric Pharmacology
  • Drug Metabolism

Background:

  • Morphine clearance in neonates and children exhibits significant developmental changes.
  • Previous models successfully scaled morphine clearance using a bodyweight-based exponential (BDE) function for specific age groups.

Purpose of the Study:

  • To characterize developmental changes in morphine clearance across the entire pediatric age range.
  • To develop and validate a model for predicting morphine clearance in neonates, infants, children, and adolescents.

Main Methods:

  • Analysis of morphine and morphine-3-glucuronide (M3G) concentration data from 358 pediatric patients and 117 adolescents using NONMEM 7.2.
  • Development of two population pharmacokinetic models: one using morphine data and another incorporating both morphine and M3G data.

Main Results:

  • The BDE model accurately described morphine clearance across the pediatric age range, with the allometric exponent decreasing sigmoidally with bodyweight.
  • In the second model, exponents for M3G formation and elimination clearance also decreased with bodyweight, indicating developmental changes in glucuronidation.
  • The BDE model eliminated the need for additional size or age parameters.

Conclusions:

  • The BDE model successfully scaled total morphine clearance and M3G-mediated glucuronidation clearance from preterm neonates to adults.
  • The model accounts for the changing allometric exponent across the pediatric age range, from values >1 in neonates to <1 in infants and children.
Abstract

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