title: PKPD model of interleukin-21 effects on thermoregulation in monkeys--application and evaluation of stochastic differential equations.
abstract: 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.
authors.affiliation: Informatics and Mathematical Modelling, Technical University of Denmark, Richard Petersens Plads, Building 321, Room 015, Kongens Lyngby 2800, Denmark. ruvo@novonordisk.com
authors.forename: Rune Viig
authors.initials: RV
authors.lastname: Overgaard
authors.forename: Nick
authors.initials: N
authors.lastname: Holford
authors.forename: Klaus A
authors.initials: KA
authors.lastname: Rytved
authors.forename: Henrik
authors.initials: H
authors.lastname: Madsen
mesh_terms: 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
chemical_list: D007378:Interleukins; D011955:Receptors, Drug; D000098546:Interleukin-21