Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This CellML model represents the "Baseline Model" in the published paper. The model runs in PCEnv and has been unit checked. All the units are balanced. Note that this model will not run in COR due to the presence of a "remainder" function. Note there are no figures in the paper showing the simuation results of this model. However we can say that the simulation output from the CellML model looks reasonable - the body temperature and metabolic rates have physiologically realistic values and oscillate over a 24 hour period according to day and night changes.
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.
model diagram
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
$\mathrm{tprime}=\mathrm{time}\times 3600\times 1\mod \mathrm{day\_length}$
$\mathrm{M\_c}=\begin{cases}\mathrm{M\_night} & \text{if $(\frac{\mathrm{tprime}}{3600}\ge \mathrm{t\_night})\land (\frac{\mathrm{tprime}}{3600}< \mathrm{t\_day})$}\\ \mathrm{M\_day} & \text{otherwise}\end{cases}$
$\frac{d M}{d \mathrm{time}}=-\mathrm{km}(M-\mathrm{M\_c})$
$\frac{d T}{d \mathrm{time}}=c^{-1}(M-k(T-\mathrm{T\_a}))$
$k=\mathrm{kb}+\mathrm{kinc}(T-\mathrm{T\_b})$
$\mathrm{T\_day}=\mathrm{T\_b}+\frac{\mathrm{delta\_T}}{2}$
$\mathrm{T\_night}=\mathrm{T\_b}-\frac{\mathrm{delta\_T}}{2}$
$\mathrm{kb}=\frac{\mathrm{M\_b}}{\mathrm{T\_b}-\mathrm{T\_a}}$
$\mathrm{M\_day}=(\mathrm{kb}+\mathrm{kinc}(\mathrm{T\_day}-\mathrm{T\_b}))(\mathrm{T\_day}-\mathrm{T\_a})$
$\mathrm{M\_night}=(\mathrm{kb}+\mathrm{kinc}(\mathrm{T\_night}-\mathrm{T\_b}))(\mathrm{T\_night}-\mathrm{T\_a})$
PKPD model of interleukin-21 effects on thermoregulation in monkeys (Baseline)
Lloyd
Catherine
May
c.lloyd@auckland@auckland.ac.nz
The University of Auckland
Auckland Bioengineering Institute
2009-10-20
The Overgaard et al. 2007 PKPD model of the effects of IL_21 on thermoregulation in monkeys
This is the CellML description of Overgaard et al.'s PKPD model of the effects of IL_21 on thermoregulation in monkeys
Catherine Lloyd
Monkey
keyword
PKPD
metabolism
thermoregulation
immunomodulation
17009101
Overgaard
Rune
Viig
Holford
Nick
Rytved
Klaus
A
Madsen
Henrik
PKPD model of interleukin-21 effects on thermoregulation in monkeys--application and evaluation of stochastic differential equations
2007-02
Pharmaceutical Research
24
298
309