Department of Pharmacy, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Gynecologic Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
BMC Cancer. 2024 Sep 27;24(1):1193. doi: 10.1186/s12885-024-12947-7.
Combining immune checkpoint and proton pump inhibitors is widely used in cancer treatment. However, the drug-drug interactions of these substances are currently unknown. This study aimed to explore drug-drug interactions associated with concomitant immune checkpoint and proton pump inhibitors.
Data were obtained from the US Food and Drug Administration Adverse Event Reporting System from 2014 to 2023. Disproportionality analysis was used for data mining by calculating the reporting odds ratios (RORs) with 95% confidence intervals (95%Cls). The adjusted RORs (RORadj) were then analysed using logistic regression analysis, considering age, sex, and reporting year. Drug-drug interactions occur when a combination treatment enhances the frequency of an event. Further confirmation of the robustness of the findings was achieved using additive and multiplicative models, which are the two statistical methodologies for signal detection of DDIs using spontaneous reporting system.
The total number of reports on immune checkpoint combined with proton pump inhibitors was 4,276. Median patient age was 66 years (interquartile range [IQR]: 60-74 years). Significant interaction signals were observed for congenital, familial and genetic disorders (RORadj = 2.66, 95%CI, 1.38-5.14, additive models = 0.7322, multiplicative models = 3.5142), hepatobiliary disorders (RORcrude = 6.64, 95%CI, 5.82-7.58, RORadj = 7.10, 95%CI, 6.16-8.18, additive models = 2.0525, multiplicative models = 1.1622), metabolism and nutrition disorders (RORcrude = 3.27, 95%CI, 2.90-3.69, RORadj = 2.66, 95%CI, 2.30-3.08, additive models = 0.6194), and skin and subcutaneous tissue disorders (RORcrude = 1.41, 95%CI, 1.26-1.58, RORadj = 1.53, 95%CI, 1.34-1.75, additive models = 0.6927, multiplicative models = 5.3599). Subset data analysis showed that programmed death-1 combined with proton pump inhibitors was associated with congenital, familial, and genetic disorders; hepatobiliary disorders; and skin and subcutaneous tissue disorders. Programmed death ligand-1 combined with proton pump inhibitors was associated with adverse reactions of metabolism and nutrition disorders. Cytotoxic T-lymphocyte antigen-4 combined with proton pump inhibitors was associated with congenital, familial, and genetic disorders, and skin and subcutaneous tissue disorders.
Based on real-world data, four Standardized MedDRA Query System Organ Class toxicities were identified as drug-drug interactions associated with combining immune checkpoint and proton pump inhibitors. Clinicians should be cautious when administering these drugs concomitantly. Preclinical trials and robust clinical studies are required to explore the mechanisms and relationships underlying interactions, thus improving understanding of drug-drug interactions associated with this combination therapy.
免疫检查点抑制剂和质子泵抑制剂联合使用在癌症治疗中广泛应用。然而，这些药物之间的药物相互作用目前尚不清楚。本研究旨在探索与免疫检查点抑制剂和质子泵抑制剂联合使用相关的药物-药物相互作用。
本研究数据来自美国食品和药物管理局 2014 年至 2023 年的不良事件报告系统。通过计算报告比值比（ROR）及其 95%置信区间（95%CI）进行数据挖掘，采用比例失衡分析。然后，使用逻辑回归分析考虑年龄、性别和报告年份，对调整后的 ROR（RORadj）进行分析。当联合治疗增加事件发生频率时，会发生药物-药物相互作用。使用附加和乘法模型进一步确认发现的稳健性，这两种统计方法是使用自发报告系统检测药物相互作用的信号的方法。
共有 4276 例关于免疫检查点联合质子泵抑制剂的报告。患者中位年龄为 66 岁（四分位距 [IQR]：60-74 岁）。显著的相互作用信号出现在先天性、家族性和遗传性疾病（RORadj=2.66，95%CI，1.38-5.14，附加模型=0.7322，乘法模型=3.5142）、肝胆疾病（RORcrude=6.64，95%CI，5.82-7.58，RORadj=7.10，95%CI，6.16-8.18，附加模型=2.0525，乘法模型=1.1622）、代谢和营养障碍（RORcrude=3.27，95%CI，2.90-3.69，RORadj=2.66，95%CI，2.30-3.08，附加模型=0.6194）和皮肤及皮下组织疾病（RORcrude=1.41，95%CI，1.26-1.58，RORadj=1.53，95%CI，1.34-1.75，附加模型=0.6927，乘法模型=5.3599）。亚组数据分析显示，程序性死亡-1 联合质子泵抑制剂与先天性、家族性和遗传性疾病、肝胆疾病和皮肤及皮下组织疾病有关；程序性死亡配体-1 联合质子泵抑制剂与代谢和营养障碍的不良反应有关；细胞毒性 T 淋巴细胞抗原-4 联合质子泵抑制剂与先天性、家族性和遗传性疾病以及皮肤和皮下组织疾病有关。
基于真实世界数据，确定了四个标准化 MedDRA 查询系统器官类别毒性作为与免疫检查点和质子泵抑制剂联合使用相关的药物-药物相互作用。临床医生在同时使用这些药物时应谨慎。需要进行临床前试验和稳健的临床研究，以探索相互作用的机制和关系，从而提高对这种联合治疗相关药物-药物相互作用的认识。
