PKPD model of interleukin-21 effects on thermoregulation in monkeys--application and evaluation of stochastic differential equations.
OBJECTIVE
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.
Overgaard
Rune Viig
RV
Informatics and Mathematical Modelling, Technical University of Denmark, Richard Petersens Plads, Building 321, Room 015, Kongens Lyngby 2800, Denmark. ruvo@novonordisk.com
Holford
Nick
N
Rytved
Klaus A
KA
Madsen
Henrik
H
D000465:Algorithms; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects*; D002940:Circadian Rhythm; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D005334:Fever / Q000517:prevention & control; D007378:Interleukins / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016013:Likelihood Functions; D008252:Macaca fascicularis; D008297:Male; D008660:Metabolism / Q000502:physiology; D015233:Models, Statistical; D011955:Receptors, Drug / Q000502:physiology; D013269:Stochastic Processes; D000098546:Interleukin-21
D007378:Interleukins; D011955:Receptors, Drug; D000098546:Interleukin-21