Population-Based Analysis of Methadone Distribution and Metabolism Using an Age-Dependent Physiologically Based Pharmacokinetic Model

Population-Based Analysis of Methadone Distribution and Metabolism Using an Age-Dependent Physiologically Based Pharmacokinetic Model

Model Status

This CellML version of the model has been checked in COR and PCEnv. It will recreate published results, although it only models a single organ (the liver) as well as the veins and arteries, and is based on a 5 year old boy. The model cannot replicate the population analysis described in the paper, which needs stochastic tools that are unavailable to CellML at present.

Model Structure

Methadone is a synthetic analgesic (painkiller) which is commonly given to both adults and children. Although methadone is commonly administered to children, the majority of the studies on methadone pharmacokinetics (PK) and pharmacodynamics (PD) have been carried out on adults. Once it has been absorbed into the systemic circulation, methadone is distributed to the brain, lungs, kidneys, muscle, liver, and intestine and it is principally metabolised in the latter two sites.

In the publication described here, Yang et al. develop a physiologically-based pharmacokinetic (PBPK) model specifically for infants aged 0-24 months old. The PBPK model includes whole body, multi-organ distribution (see the figure below), plasma protein binding, metabolism, and clearance, and its parameters are based on a database of pediatric pharmacokinetics parameters and data collected from clinical experiments. The model is further supported by data from individual adults, and is then scaled to be suitable for children aged 0-24 months old.

The model simulations predict there are large variations in plasma concentrations and clearance kinetics for methadone amongst children.

The complete original paper reference is cited below:

Population-based analysis of methadone distribution and metabolism using an age-dependent physiologically based pharmacokinetic model, Feng Yang, Xianping Tong, D. Gail. McCarver, Ronald N. Hines and Daniel A. Beard, 2006, Journal of Pharmacokinetics and Pharmacodynamics , volume 33, issue 4. (a PDF versions of the article are available on the Journal of Pharmacokinetics and Pharmacodynamics website.) PubMed ID: 16758333

Schematic diagram of a PBPK model consisting of 17 compartments. The lines represent blood flow while the boxes represent organs or systems. Methadone is primarily metabolised in the liver and gastro-intestinal (GI) system, while its elimination mainly occurs through the kidneys. Organs in which methadone are not distributed include skin, adipose, thyroid, pancreas, and bone marrow are grouped together as others.