Mining And Analysis Of Adverse Reaction Signals Of Immune Checkpoint Inhibitors

Object:To analyze the Adverse drug reactions/events（ADR/ADE）reports of a hospital from 2019-2021and summarize the characteristics and trends of drug ADR/ADE occurrence.To evaluate the safety data of immune checkpoint inhibitors（ICI）when used alone/in combination after marketing,to summarize the risk signals of high incidence,high correlation and new adverse drug reactions（ADR）,and to analyze the main system organs involved and the The data of ADRs are summarized to provide a reference basis for the safe clinical use of drugs.Methods:Retrospective analysis was used to log in to the national adverse drug reaction monitoring system and retrieve ADRs/ADEs reported from January 1,2019 to December 31,2021 in a hospital,and Microsoft Office Excel 2019 was used to statistically analyze patients with ADRs/ADEs in the hospital in terms of gender,age,drug type,and system organs mainly involved in ADRs/ADEs.Adverse event reports for anti-PD-1,anti-PD-L1,and anti-CTLA-4 2016-2021 were collected through the FAERS database.Data were organized,cleaned,and normalized using Microsoft Office Excel 2019 and the Medical dictionary for regulatory activities（Med DRA）.Analysis of data variance was performed using SPSS 26.0 using chi-square test（Chi-square test）with a significant difference of P<0.05.The report odds ratio（ROR）,proportional rate reduction（PRR）,and Medicines and Healthcare Products Regulatory Agency（MHRA）were used to screen the top 30 ranking of occurrence cases and signal intensity and new ADR risk signals not mentioned in the instruction manual,and the ADRs with signals were imported into Med DRA for system and organ classification,and Origin 2018 was used to screen major and characteristic system organs by drawing bar-fold plots conditional on signal values and occurrence cases,and to screen high-risk ADRs by drawing color mapping bubble plots conditional on log₂ROR,the radical sign of Chi-square value X and occurrence cases.Results:1.In the retrospective analysis,the results of the analysis of the 1671 reports included yielded that male patients（53.38%）had more adverse drug reactions than female patients（46.62%）,age was mainly concentrated in the group of people≥51 years old,intravenous drip（46.20%）route of administration was predominant,oncology medication resulted in the highest adverse reactions,and the main system organ involved was damage to the gastrointestinal system.2.ICI monotherapy:（1）Basic information:The incidence of adverse reactions was higher in all male patients than in female patients（P<0.05）,and the age distribution was mainly in the group of≥65years old（P<0.05）,and the types of serious ADRs were mainly hospitalization or prolongation,death and disability,etc.The reported countries were mainly the United States,Japan and Germany.（2）Anti-PD-1 drugs:new ADRs for Pleural effusion,Lichenoid keratosis,and urinary tract infection were unearthed.anti-PD-1 drug ADR signals were mainly concentrated in systems such as hepatobiliary diseases,endocrine disorders,and skin and subcutaneous tissue diseases.Further excavation and analysis yielded high-risk ADR signals such as sclerosing cholangitis,cholangitis,vitiligo,Pemphigoid,and infectious seroma.（3）Anti-PD-L1 drugs:new ADRs such as Pemphigoid,alveolar hemorrhage,plagioretinal detachment,and peripheral neuropathy were unearthed.anti-PD-L1 drug ADR signals were mainly concentrated in cardiac disease,neurological system,and other systems.The analysis yielded high-risk ADR signals such as duodenal perforation,myocarditis,autoimmune encephalitis,and febrile neutropenia.（4）Anti-CTLA-4 drugs:new ADR signals for sepsis and pancreatitis were tapped.The anti-CTLA-4 drug ADR signals were mainly concentrated in endocrine disorders and gastrointestinal disease systems.Pituitary inflammation,hypopituitarism,and colitis are high-risk ADR signals.3.ICI combination therapy（1）Base case:similar outcome to monotherapy.（2）Anti-PD-1 drugs combined with anti-CTLA-4 drugs:Ipilimumab combined with Nivolumab tapped new ADR signals such as hyponatremia and pleural effusion,and Ipilimumab combined with Pembrolizumab occurred more common ADR signals in colitis and vitiligo.Anti-PD-1 combined with anti-CTLA-4 ADR signals were focused on hepatobiliary diseases,endocrine disorders,and gastrointestinal diseases.Analysis yielded high-risk ADR signals for immune-mediated hepatitis,abnormal liver function,and Hypophysitis.（3）Anti-PD-L1 combined with anti-CTLA-4 class of drugs:Tremelimumab combined with Durvalumab tapped new ADR signals such as sepsis and muscle weakness,and Ipilimumab combined with Atezolizumab occurred nephritis,myositis,more commonly.Anti-PD-L1 combined with anti-CTLA-4ADR signals were mainly focused on infections and infestations,blood and lymphatic system disorders.Analysis yielded biliary tract infections,febrile neutropenia as high-risk ADR signals.Conclusion:1.the basic situation:（1）The occurrence of adverse reactions in men is higher than that in women,and individual differences should be noted in the clinical use of drugs.（2）Adverse reactions are more likely to occur in people aged≥51 years old,and more attention should be paid to this group of people.（3）The incidence of adverse reactions to new antineoplastic drugs ranks high,and the safety risk monitoring of such drugs should be strengthened.2.Data mining:（1）The adverse reactions of new antineoplastic drugs ICI involve multiple system organs,and we should be highly alert to the excavation of new adverse reactions and the characteristic system organs with high risk ADRs.（2）There is uniformity and variability in the system organs where the ADRs caused by ICI drugs are mainly concentrated.（3）The excavation of ADRs with high incidence and strong correlation can provide reference for safe clinical use.