Department of Pharmacy, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatric, Chongqing, 400014, China.
School of Pharmacy, Chongqing Medical University, Chongqing, 400016, China.
Clin Drug Investig. 2019 Mar;39(3):319-330. doi: 10.1007/s40261-018-0735-0.
Immune checkpoint inhibitors (ICIs)-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1) monoclonal antibodies (mAbs)-either as single agents or in combination have become the standard of care for an increasing number of indications. Understanding both the ICI-associated adverse events (AEs) and the possible rank-order of these drugs in terms of susceptibility is essential if we are to improve the curative effect and reduce toxicity.
We detected signals of the AEs of ICIs by data mining using the US Food and Drug Administration (FDA) AEs Reporting System (FAERS) database. The definition relied on the preferred terms (PTs) and the standardized MedDRA Queries (SMQs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Disproportionality analysis was performed by calculating the reporting odds ratios (ROR) with 95% confidence intervals (CIs).
Adverse effects of CTLA-4 and PD-1 mAbs were most commonly observed in the skin, gastrointestinal tract, endocrine systems, liver, and lung, and they included rash, diarrhea, colitis, and thyroid dysfunction. Thyroid dysfunction, type 1 diabetes mellitus, and pneumonitis were more closely associated with the use of anti-PD-1, whereas colitis, diarrhea, hypophysitis, and adrenal insufficiency were more closely associated with anti-CTLA-4; rash and hepatitis occurred similarly in both. Disproportionality signals for less common AEs in other organ systems, including the renal, neurological, cardiac, ocular, musculoskeletal, and hematologic systems, were also detected. Nivolumab and pembrolizumab have very similar safety profiles, but the signal strength of AEs increased when combined with ipilimumab.
The results of this study are in agreement with clinical observations, suggesting the usefulness of pharmacovigilance in "real-world" safety monitoring.
免疫检查点抑制剂（ICI）-细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）和程序性死亡受体 1（PD-1）单克隆抗体（mAb）-无论是单药治疗还是联合治疗，已经成为越来越多适应证的标准治疗方法。如果要提高疗效并降低毒性，了解 ICI 相关不良事件（AE）以及这些药物在易感性方面的可能等级顺序至关重要。
我们使用美国食品和药物管理局（FDA）不良事件报告系统（FAERS）数据库，通过数据挖掘来检测 ICI 的 AE 信号。该定义依赖于监管活动医学词典（MedDRA）提供的首选术语（PT）和标准化 MedDRA 查询（SMQ）。通过计算报告比值比（ROR）及其 95%置信区间（CI）进行比例失衡分析。
CTLA-4 和 PD-1 mAb 的不良作用最常发生于皮肤、胃肠道、内分泌系统、肝脏和肺部，包括皮疹、腹泻、结肠炎、甲状腺功能障碍。甲状腺功能障碍、1 型糖尿病和肺炎与抗 PD-1 的使用更密切相关，而结肠炎、腹泻、垂体炎和肾上腺功能不全与抗 CTLA-4 更密切相关；皮疹和肝炎在两者中发生的频率相似。在其他器官系统，包括肾脏、神经、心脏、眼部、肌肉骨骼和血液系统中，也检测到了不太常见的 AE 的比例失衡信号。纳武利尤单抗和帕博利珠单抗具有非常相似的安全性特征，但与伊匹单抗联合使用时，AE 的信号强度增加。
这项研究的结果与临床观察一致，表明药物警戒在“真实世界”安全性监测中的有用性。
