Overgaard Rune Viig, Holford Nick, Rytved Klaus A, Madsen Henrik
Informatics and Mathematical Modelling, Technical University of Denmark, Richard Petersens Plads, Building 321, Room 015, Kongens Lyngby 2800, Denmark.
Pharm Res. 2007 Feb;24(2):298-309. doi: 10.1007/s11095-006-9143-x. Epub 2006 Sep 29.
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.
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.
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.
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.
利用热调节的基本机制，描述重组人白细胞介素-21（IL-21）对食蟹猴核心体温的药效学作用。主要致力于比较在药代动力学药效学（PKPD）建模中常微分方程（ODE）与随机微分方程（SDE）的使用情况。
构建一个包括昼夜节律、新陈代谢、热量散失和体温调节设定点的温度模型。该模型基于使用NONMEM的SDE被构建为一个混合效应模型。
IL-21的作用在于设定点和新陈代谢的昼夜节律。该模型能够描述一组复杂的IL-21诱导现象，包括1）昼夜节律消失，2）首剂后无作用，以及3）第二剂后高变异性。SDE提供了更符合实际的描述以及改善的模拟特性，并进一步将模型转变为一个不能被自相关函数证伪的模型。
IL-21对食蟹猴体温调节的诱导作用由一个生物学上合理的模型解释。通过使用SDE提高了模型质量。
