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

Research output: Contribution to journalJournal article – Annual report year: 2007Researchpeer-review

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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.
Original languageEnglish
JournalPharmaceutical Research
Volume24
Issue number2
Pages (from-to)298-309
ISSN0724-8741
DOIs
Publication statusPublished - 2007
CitationsWeb of Science® Times Cited: No match on DOI

    Research areas

  • SDE, PKPD model, statistical model, autocorrelation, immunomodulation, thermoregulation
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