Fraunhofer-Chalmers Centre, Chalmers Science Park, 412 88 Gothenburg, Sweden.; Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, 412 96 Gothenburg, Sweden..
Grünenthal GmbH, Aachen, Germany.
Eur J Pharm Sci. 2021 Oct 1;165:105937. doi: 10.1016/j.ejps.2021.105937. Epub 2021 Jul 11.
This study presents a non-linear mixed effects model describing tumour necrosis factor alpha (TNFα) release after lipopolysaccharide (LPS) provocations in absence or presence of anti-inflammatory test compounds. Inter-occasion variability and the pharmacokinetics of two test compounds have been added to this second-generation model, and the goal is to produce a framework of how to model TNFα response in LPS challenge studies in vivo and demonstrate its general applicability regardless of occasion or type of test compound. Model improvements based on experimental data were successfully implemented and provided a robust model for TNFα response after LPS provocation, as well as reliable estimates of the median pharmacodynamic parameters. The two test compounds, Test Compound A and roflumilast, showed 81.1% and 74.9% partial reduction of TNFα response, respectively, and the potency of Test Compound A was estimated to 0.166 µmol/L. Comparing this study with previously published work reveals that our model leads to biologically reasonable output, handles complex data pooled from different studies, and highlights the importance of accurately distinguishing the stimulatory effect of LPS from the inhibitory effect of the test compound.
本研究提出了一个描述脂多糖 (LPS) 激发后肿瘤坏死因子 α (TNFα) 释放的非线性混合效应模型，在该模型中不存在或存在抗炎测试化合物。本研究将两种测试化合物的个体间变异性和药代动力学加入到第二代模型中，目的是建立一种在 LPS 挑战研究中如何模拟 TNFα 反应的框架，并证明其无论在何种情况下或测试化合物的类型如何都具有普遍适用性。基于实验数据的模型改进得到了成功实施，并为 LPS 激发后 TNFα 反应提供了一个稳健的模型，以及对中位药效学参数的可靠估计。两种测试化合物，测试化合物 A 和罗氟司特，分别显示出 81.1%和 74.9%的 TNFα 反应部分抑制，并且测试化合物 A 的效价估计为 0.166µmol/L。将本研究与之前发表的工作进行比较表明，我们的模型产生了合理的生物学输出，处理了来自不同研究的复杂数据，并强调了准确区分 LPS 的刺激作用和测试化合物的抑制作用的重要性。
