PKPD model of interleukin-21 effects on thermoregulation in monkeys (Pharmacodynamic)

PKPD model of interleukin-21 effects on thermoregulation in monkeys--application and evaluation of stochastic differential equations

Model Status

This CellML model represents the "Pharmacodynamic Model" in the published paper. The model runs in PCEnv to recreate figure3 in the published paper. The units have been chaecked and they balance. Note that this model will not run in COR due to the presence of a "remainder" function. Please also note that we have chosen "high dose levels" (deltahigh_dose=1), and IL-21 is administered on days 1, 3 and 5, at a dose of 3mg/kg. The f2 function in equation 3 of the paper has been ignored as this is only relevant for drugs directly affecting heat conduction, which IL-21 is not expected to. Thank you to the original model author Rune Viig Overgaard for providing us with the NONMEM code and for clarifying certain aspects of the model.

Model Structure

ABSTRACT: PURPOSE: To describe the pharmacodynamic effects of recombinant human interleukin-21 (IL-21) on core body temperature in cynomolgus monkeys using basic mechanisms of heat regulation. A major effort was devoted to compare the use of ordinary differential equations (ODEs) with stochastic differential equations (SDEs) in pharmacokinetic pharmacodynamic (PKPD) modelling. METHODS: A temperature model was formulated including circadian rhythm, metabolism, heat loss, and a thermoregulatory set-point. This model was formulated as a mixed-effects model based on SDEs using NONMEM. RESULTS: The effects of IL-21 were on the set-point and the circadian rhythm of metabolism. The model was able to describe a complex set of IL-21 induced phenomena, including 1) disappearance of the circadian rhythm, 2) no effect after first dose, and 3) high variability after second dose. SDEs provided a more realistic description with improved simulation properties, and further changed the model into one that could not be falsified by the autocorrelation function. CONCLUSIONS: The IL-21 induced effects on thermoregulation in cynomolgus monkeys are explained by a biologically plausible model. The quality of the model was improved by the use of SDEs.

Schematic diagram of the model for IL-21 induced regulation of core body temperature.

The original paper reference is cited below:

PKPD model of interleukin-21 effects on thermoregulation in monkeys - application and evaluation of stochastic differential equations, Rune Viig Overgaard, Nick Holford, Klaus A. Rytved and Henrik Madsen, 2007, Pharmaceutical Research, 24, (2), 298-309. PubMed ID: 17009101