PKPD model of interleukin-21 effects on thermoregulation in monkeys - Application and evaluation of stochastic differential equations
2007 (English)In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 24, no 2, 298-309 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 24, no 2, 298-309 p.
autocorrelation, immunomodulation, PKPD model, SDE, statistical model, thermoregulation
IdentifiersURN: urn:nbn:se:uu:diva-146500DOI: 10.1007/s11095-006-9143-xISI: 000243398900009PubMedID: 17009101OAI: oai:DiVA.org:uu-146500DiVA: diva2:398262