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Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database.

ABSTRACT: Purpose: The aim of our study was to characterize the clinical features of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database.

Methods: The irAEs were defined using the preferred terms of the Medical Dictionary for Regulatory Activities. irAEs were categorized as follows: adrenal insufficiency, colitis, eye diseases, hematological disorder, hepatitis, hyperthyroidism, hypopituitarism, hypothyroidism, myasthenia gravis, myocarditis, nephritis/renal dysfunction, pneumonitis, rash, and type 1 diabetes mellitus. We used several indices such as reporting odds ratio (ROR) to assess disproportionality in pharmacovigilance data, time-to-onset analysis using Weibull shape parameters, and the association rule mining technique to evaluate possible risk factors between variables in the spontaneous reporting system database.

Results: The JADER database contained 534?688 reports from April 2004 to June 2018. The RORs of pneumonitis including interstitial lung disease for nivolumab, pembrolizumab, and ipilimumab were 7.02 (95% confidence interval: 6.55-7.52), 9.08 (8.28-9.97), and 1.74 (1.27-2.38), respectively. The median onsets (quartiles, 25-75%) of myocarditis caused by nivolumab and pembrolizumab were 28.0 (15.5-60.5) and 18.0 (13.0-44.5) days, respectively. Co-therapy with nivolumab and ipilimumab may be associated with irAEs in several categories as per the association rule mining analysis.

Conclusion: Our results demonstrated a potential risk of irAEs associated with ICIs, based on RORs and time-to-onset analysis. Furthermore, our findings indicated that patients receiving nivolumab and ipilimumab as co-therapy should be carefully monitored.

SUBMITTER: Hasegawa S

PROVIDER: S-EPMC7692939 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database.

Hasegawa Shiori S Ikesue Hiroaki H Nakao Satoshi S Shimada Kazuyo K Mukai Ririka R Tanaka Mizuki M Matsumoto Kiyoka K Inoue Misaki M Satake Riko R Yoshida Yu Y Goto Fumiya F Hashida Tohru T Nakamura Mitsuhiro M

Pharmacoepidemiology and drug safety 20200901 10

<h4>Purpose</h4>The aim of our study was to characterize the clinical features of immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database.<h4>Methods</h4>The irAEs were defined using the preferred terms of the Medical Dictionary for Regulatory Activities. irAEs were categorized as follows: adrenal insufficiency, colitis, eye diseases, hematological disorder, hepatitis, hyperthy ...[more]

PMID: 32869941

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Project description:Objectives:Platinum compounds cause several adverse events, such as nephrotoxicity, gastrointestinal toxicity, myelosuppression, ototoxicity, and neurotoxicity. We evaluated the incidence of renal impairment as adverse events are related to the administration of platinum compounds using the Japanese Adverse Drug Event Report database. Methods:We analyzed adverse events associated with the use of platinum compounds reported from April 2004 to November 2016. The reporting odds ratio at 95% confidence interval was used to detect the signal for each renal impairment incidence. We evaluated the time-to-onset profile of renal impairment and assessed the hazard type using Weibull shape parameter and used the applied association rule mining technique to discover undetected relationships such as possible risk factor. Results:In total, 430,587 reports in the Japanese Adverse Drug Event Report database were analyzed. The reporting odds ratios (95% confidence interval) for renal impairment resulting from the use of cisplatin, oxaliplatin, carboplatin, and nedaplatin were 2.7 (2.5-3.0), 0.6 (0.5-0.7), 0.8 (0.7-1.0), and 1.3 (0.8-2.1), respectively. The lower limit of the reporting odds ratio (95% confidence interval) for cisplatin was >1. The median (lower-upper quartile) onset time of renal impairment following the use of platinum-based compounds was 6.0-8.0?days. The Weibull shape parameter ? and 95% confidence interval upper limit of oxaliplatin were <1. In the association rule mining, the score of lift for patients who were treated with cisplatin and co-administered furosemide, loxoprofen, or pemetrexed was high. Similarly, the scores for patients with hypertension or diabetes mellitus were high. Conclusion:Our findings suggest a potential risk of renal impairment during cisplatin use in real-world setting. The present findings demonstrate that the incidence of renal impairment following cisplatin use should be closely monitored when patients are hypertensive or diabetic, or when they are co-administered furosemide, loxoprofen, or pemetrexed. In addition, healthcare professionals should closely assess a patient's background prior to treatment.

Project description:BackgroundAlthough arrhythmias have been reported in patients treated with immune checkpoint inhibitors (ICIs), the association between arrhythmias and ICIs has not been thoroughly evaluated in real-world studies. We aimed to describe the major features of ICI-related arrhythmic events and identify the factors that contributed to death.MethodsA disproportionality analysis was performed using data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 2011 to December 2021. Reporting odds ratios (RORs), proportional reporting ratio and information component were used to assess whether adverse arrhythmic events were associated with ICIs. The clinical characteristics of patients with ICI-associated arrhythmias were compared with fatal and non-fatal arrhythmias. The time to onset (TTO), fatality rates of arrhythmic events were also investigated.ResultsWe identified a total of 1945 cases of ICI-related arrhythmic events. Men (64.78%) were identified significantly more frequently than women (28.84%). The median age was 68 years ([interquartile range, IQR] 60-75 years). Anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand-1 (PD-L1) were associated with adverse arrhythmic events, corresponding to ROR 1.11 (95% confidence interval [CI] 1.05-1.17) and ROR 1.34 (95% CI 1.20-1.49), respectively. However, anti-cytotoxic T-lymphocyte associated protein 4 or combination immunotherapy did not appear to be associated with arrhythmic events. Atrial fibrillation (N = 576, 0.62%), cardiac arrest (N = 284, 0.31%), tachycardia (N = 175, 0.19%) were the most common adverse arrhythmic events. Sudden death and complete atrioventricular block are adverse events that are significantly associated with ICI-related arrhythmic events and have strong signal intensity. The TTO of cases that resulted in death (30 days [IQR] 11-73.75) was significantly earlier than that of cases that did not result in death (33 days [IQR 10.5-88.5], p = 0.003). ICI-related arrhythmic events were severe with death occurring in 507 (26.07%) of 1945 arrhythmias cases.ConclusionsTreatment with PD-1/PD-L1 may cause arrhythmic events, which are severe and tend to occur early on during treatment. It is important to identify ICI-related arrhythmias as early as possible, and to manage them appropriately.

Dataset Information

Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database.

Publications

Analysis of immune-related adverse events caused by immune checkpoint inhibitors using the Japanese Adverse Drug Event Report database.

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