Departments of Drug Metabolism and Pharmacokinetics (H.W., L.L., Y.D., M.R.W., C.E.C.A.H.) and Immunology (W.O.), Genentech Inc., South San Francisco, California
Departments of Drug Metabolism and Pharmacokinetics (H.W., L.L., Y.D., M.R.W., C.E.C.A.H.) and Immunology (W.O.), Genentech Inc., South San Francisco, California.
J Pharmacol Exp Ther. 2019 Jun;369(3):406-418. doi: 10.1124/jpet.118.255562. Epub 2019 Apr 2.
The ability of rodent immune-mediated arthritis models to quantitatively predict therapeutic activity of antiarthritis agents is poorly understood. Two commonly used preclinical models of arthritis are adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) in rats. The objective of the current study is to investigate the relationship between efficacy in AIA and CIA in rats, and clinical efficacy in rheumatoid arthritis patients using translational pharmacokinetic-pharmacodynamic (PK-PD) analysis. A range of doses of indomethacin (a nonsteroidal anti-inflammatory drug), and three disease-modifying antirheumatic drugs (DMARDs), methotrexate, etanercept, and tofacitinib, were evaluated in AIA and CIA rats. Dexamethasone was included in this study as a positive control. The area under the ankle diameter-time profile (AUC) and ankle histopathology summed scores (AHSS) were used as efficacy endpoints for activity against disease symptoms (joint inflammation) and disease progression (joint damage), respectively. Translational PK-PD analysis was performed to rank order preclinical efficacy endpoints at clinically relevant concentrations. For each drug tested, inhibition of AUC and AHSS scores was generally comparable in both magnitude and rank order. Overall, based on both AUC and the AHSS inhibition, the rank ordering of preclinical activity for the DMARDs evaluated was tofacitinib > etanercept ≥ methotrexate. This ranking of preclinical efficacy was consistent with reported clinical efficacy. Of interest, indomethacin showed equal or often better efficacy than the three DMARDs evaluated on inhibiting AHSS despite having limited ability to prevent joint damage clinically in patients. The translational value of performing PK-PD analysis of arthritis models in rats is discussed.
啮齿动物免疫介导性关节炎模型定量预测抗关节炎药物治疗活性的能力尚未得到充分理解。两种常用的关节炎临床前模型为大鼠佐剂诱导性关节炎（AIA）和胶原诱导性关节炎（CIA）。本研究的目的是通过转化药代动力学-药效学（PK-PD）分析，研究大鼠 AIA 和 CIA 中的疗效与类风湿关节炎患者的临床疗效之间的关系。评估了吲哚美辛（一种非甾体抗炎药）和三种疾病修饰抗风湿药物（DMARDs），即甲氨蝶呤、依那西普和托法替尼在 AIA 和 CIA 大鼠中的剂量范围。地塞米松被包括在本研究中作为阳性对照。踝关节直径时间曲线下面积（AUC）和踝关节组织病理学总和评分（AHSS）分别作为针对疾病症状（关节炎症）和疾病进展（关节损伤）的疗效终点。进行转化 PK-PD 分析，以对临床相关浓度下的临床前疗效终点进行排序。对于所测试的每种药物，AUC 和 AHSS 评分的抑制作用在幅度和排序上通常是可比的。总体而言，基于 AUC 和 AHSS 抑制，所评估的 DMARDs 的临床前活性排序为托法替尼>依那西普≥甲氨蝶呤。这种临床前疗效的排序与报告的临床疗效一致。有趣的是，尽管在临床上治疗患者关节损伤的能力有限，但与所评估的三种 DMARDs 相比，吲哚美辛在抑制 AHSS 方面表现出相等或通常更好的疗效。讨论了在大鼠中进行关节炎模型 PK-PD 分析的转化价值。
