Institute of Infection, Immunity and Inflammation, University of Glasgow, University Avenue, Glasgow, G128QQ, UK.
Eli Lilly and Company, Indianapolis, IN, USA.
Arthritis Res Ther. 2019 Aug 2;21(1):183. doi: 10.1186/s13075-019-1964-1.
The in vitro pharmacology of baricitinib, upadacitinib, and tofacitinib was evaluated to understand differences among these JAK inhibitors (JAKis) at the cellular level.
Peripheral blood mononuclear cells from healthy donors were incubated with different JAKis, levels of phosphorylated signal transducer and activator of transcription (pSTAT) were measured following cytokine stimulation, and half maximum inhibitory concentration (IC) values were calculated in phenotypically gated leukocyte subpopulations. Therapeutic dose relevance of the in vitro analysis was assessed using calculated mean concentration-time profiles over 24 h obtained from JAKi-treated subjects. Time above IC and average daily percent inhibition of pSTAT formation were calculated for each JAKi, cytokine, and cell type.
Distinct JAKis displayed different in vitro pharmacologic profiles. For example, tofacitinib and upadacitinib were the most potent inhibitors of the JAK1/3-dependent cytokines tested (interleukin [IL]-2, IL-4, IL-15, and IL-21) with lower IC values and increased time above IC translating to a greater overall inhibition of STAT signaling during the dosing interval. All JAKis tested inhibited JAK1/2-dependent cytokines (e.g., IL-6 and interferon [IFN]-γ), the JAK1/tyrosine kinase 2 (TYK2)-dependent cytokines IL-10 and IFN-α, the JAK2/2-dependent cytokines IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), and the JAK2/TYK2-dependent cytokine granulocyte colony-stimulating factor (G-CSF), but often to significantly differing degrees.
Different JAKis modulated distinct cytokine pathways to varying degrees, and no agent potently or continuously inhibited an individual cytokine signaling pathway throughout the dosing interval. Notably, baricitinib inhibited JAK1/3 signaling to a lesser extent than upadacitinib and tofacitinib, while upadacitinib, baricitinib, and tofacitinib inhibited the signaling of JAK2/2-dependent cytokines, including GM-CSF and IL-3, as well as the signaling of the JAK2/TYK2-dependent cytokine G-CSF.
评估巴瑞替尼、乌帕替尼和托法替布的体外药理学，以了解这些 JAK 抑制剂（JAKi）在细胞水平上的差异。
用不同的 JAKi 孵育健康供者外周血单个核细胞，在细胞因子刺激后测量磷酸化信号转导和转录激活因子（pSTAT）的水平，并计算表型门控白细胞亚群的半最大抑制浓度（IC）值。使用从 JAKi 治疗的受试者中获得的 24 小时平均浓度-时间曲线计算体外分析的治疗剂量相关性。计算每种 JAKi、细胞因子和细胞类型的 IC 以上时间和 pSTAT 形成的平均每日百分比抑制率。
不同的 JAKi 显示出不同的体外药理学特征。例如，托法替布和乌帕替尼是测试的 JAK1/3 依赖性细胞因子（白细胞介素[IL]-2、IL-4、IL-15 和 IL-21）中最有效的抑制剂，IC 值较低，IC 以上时间延长，这意味着在给药间隔期间对 STAT 信号的总体抑制作用更大。所有测试的 JAKi 均抑制 JAK1/2 依赖性细胞因子（如 IL-6 和干扰素[IFN]-γ）、JAK1/酪氨酸激酶 2（TYK2）依赖性细胞因子 IL-10 和 IFN-α、JAK2/2 依赖性细胞因子 IL-3 和粒细胞-巨噬细胞集落刺激因子（GM-CSF）以及 JAK2/TYK2 依赖性细胞因子粒细胞集落刺激因子（G-CSF），但往往程度不同。
不同的 JAKi 以不同程度调节不同的细胞因子途径，并且没有一种药物在整个给药间隔内强力或持续地抑制单个细胞因子信号通路。值得注意的是，巴瑞替尼对 JAK1/3 信号的抑制作用小于乌帕替尼和托法替布，而乌帕替尼、巴瑞替尼和托法替布抑制 JAK2/2 依赖性细胞因子（包括 GM-CSF 和 IL-3）的信号以及 JAK2/TYK2 依赖性细胞因子 G-CSF 的信号。
