Laurent Léonard, Abbar Baptiste, Bihan Kevin, Dumas Elise, Jochum Floriane, Lebrun-Vignes Bénédicte, Spano Jean-Philippe, Salem Joe-Elie, Hamy Anne-Sophie, Reyal Fabien, Gougis Paul
Residual Tumor & Response to Treatment Laboratory, RT2Lab, INSERM, U932 Immunity and Cancer, Institut Curie, Université Paris Cité, Paris, France.
Department of Medical Oncology, Pitié-Salpêtrière Hospital, Sorbonne Université, Assistance Publique - Hôpitaux de Paris (AP-HP), Paris, France.
Clin Pharmacol Ther. 2025 Jun 16;118(3):593-9. doi: 10.1002/cpt.3721.
Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment but are responsible for various immune-related adverse events (irAE). The impact of non-anticancer medications (comedications) on irAE occurrence remains largely unexplored. The objective of this study was to assess comedications associated with an increased reporting of irAE with ICIs. In this pharmacovigilance study, all individual case safety reports (ICSRs) involving ICIs reported in the World Health Organization international pharmacovigilance database Vigibase up to January 2024 were extracted. All suspect or interacting comedications were analyzed individually and as drug classes using Anatomical Therapeutic Chemical classification level 4. The primary outcome was the reporting odds ratio (ROR) of irAE in patients who received both an ICI and the comedication of interest, compared with ICI-treated patients who did not receive that comedication. Among 169,753 ICSRs involving an ICI, a total of 314,366 comedications were recorded, with 8,122 identified as "suspect or interacting." Analysis shows an increased reporting of nephritis with proton pump inhibitors (PPI) (ROR = 29.62 [95% CI = 18.61-47.14]) and with non-steroidal anti-inflammatory drugs (ROR = 10.47 [95% CI = 4.15-26.41]), myositis with statins (ROR = 9.41 [95% CI = 3.50-25.30]), ketoconazole with hepatitis (ROR = 20.49 [95% CI = 1.53-274.17]) and autoimmune bullous disease with dipeptyl-peptidase-4 inhibitors (ROR = 46.42 [95% CI = 11.71-184.05]), among others. Various drugs, including PPI (ROR = 8.61 [95% CI = 3.48-21.26]), some anti-infectives (sulfamethoxazole, ROR = 31.31 [95% CI = 13.32-73.61], clavulanic acid, ROR = 18.12 [95% CI = 4.77-68.89]), allopurinol (ROR = 57.11 [95% CI = 11.27-289.39]) or levetiracetam (ROR = 14.91 [95% CI = 2.15-103.64]) were associated with serious cutaneous adverse reactions. Complementary analysis showed higher ROR in the ICI population versus without ICI for the association of nephritis with ibuprofen (ROR = 27.82 vs. ROR = 3.56, ROR = 7.81 [95% CI = 1.23-49.50]) and myocarditis with influenza vaccine (ROR = 22.74 vs. ROR = 0.66, ROR = 34.45 [95% CI = 1.66-723.24]), suggesting a synergistic toxicity. This study identified multiple comedications associated with an increased reporting of specific irAE. Some of them might be synergistic warranting further investigation.
免疫检查点抑制剂（ICI）彻底改变了癌症治疗方式，但会引发各种免疫相关不良事件（irAE）。非抗癌药物（合并用药）对irAE发生的影响在很大程度上仍未得到充分研究。本研究的目的是评估与ICI导致irAE报告增加相关的合并用药。在这项药物警戒研究中，提取了截至2024年1月在世界卫生组织国际药物警戒数据库Vigibase中报告的所有涉及ICI的个体病例安全报告（ICSR）。所有可疑或相互作用的合并用药均按照解剖治疗化学分类第4级单独及作为药物类别进行分析。主要结局是接受ICI和相关合并用药的患者发生irAE的报告比值比（ROR），并与未接受该合并用药的ICI治疗患者进行比较。在169,753份涉及ICI的ICSR中，共记录了314,366种合并用药，其中8,122种被确定为“可疑或相互作用”。分析显示，质子泵抑制剂（PPI）（ROR = 29.62 [95% CI = 18.61 - 47.14]）和非甾体抗炎药（ROR = 10.47 [95% CI = 4.15 - 26.41]）与肾炎报告增加相关，他汀类药物与肌炎（ROR = 9.41 [95% CI = 3.50 - 25.30]）相关，酮康唑与肝炎（ROR = 20.49 [95% CI = 1.53 - 274.17]）相关，二肽基肽酶-4抑制剂与自身免疫性大疱性疾病（ROR = 46.42 [95% CI = 11.71 - 184.05]）相关等。包括PPI（ROR = 8.61 [95% CI = 3.48 - 21.26]）、一些抗感染药物（磺胺甲恶唑，ROR = 31.31 [95% CI = 13.32 - 73.61]，克拉维酸，ROR = 18.12 [95% CI = 4.77 - 68.89]）、别嘌醇（ROR = 57.11 [95% CI = 11.27 - 289.39]）或左乙拉西坦（ROR = 14.91 [95% CI = 2.15 - 103.64]）在内的多种药物与严重皮肤不良反应相关。补充分析显示，在ICI人群中，与布洛芬相关的肾炎（ROR = 27.82 vs. ROR = 3.56，ROR = 7.81 [95% CI = 1.23 - 49.50]）和与流感疫苗相关的心肌炎（ROR = 22.74 vs. ROR = 0.66，ROR = 34.45 [95% CI = 1.66 - 723.24]）的ROR高于无ICI人群，提示存在协同毒性。本研究确定了多种与特定irAE报告增加相关的合并用药。其中一些可能具有协同作用，值得进一步研究。
