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Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase.

ABSTRACT: PURPOSE:Our study aimed to map endocrine toxicity spectrum of immune checkpoint inhibitors (ICIs). METHODS:We obtained data from VigiBase, between January 1, 2011 and March 6, 2019. All endocrine adverse drug reactions (ADRs) were classified by group queries according to the Medical Dictionary for Regulatory Activities. Disproportionality analysis was performed with information component (IC) and reporting odds ratio (ROR). We used IC to identify meaningful endocrinopathies associated with ICIs and ROR to compare differences between ICI subgroups of ADRs. IC025 (lower end of the 95% confidence interval of IC) is considered significant if larger than 0. RESULTS:In all, 6089 reports for endocrinopathies associated with ICIs were involved, with a male to female ratio of 1.5:1. The disproportionality analysis indicated significance of not only common endocrinopathies: thyroid dysfunction, hypophysitis/hypopituitarism, adrenal insufficiency, T1DM, fulminant T1DM (IC025: 4.12-6.62), but also rare endocrinopathies: hypoparathyroidism, diabetes insipidus, hypogonadism (IC025: 1.56-2.04). Increased risk of ADR reporting emerged in anti-CTLA-4 (e.g., hypophysitis/hypopituitarism, adrenal insufficiency) or in anti-PD-1/PD-L1 (e.g., thyroid dysfunction, T1DM, fulminant T1DM). In general, combination therapy (anti-CTLA-4 plus anti-PD-1/PD-L1) had a stronger association with endocrinopathies than monotherapy (ROR: 2.8, 95% CI: 2.5-3.1). Onset time of common endocrinopathies differed between different ICI therapies, typically within 12 weeks in anti-CTLA-4 monotherapy but diffusely ranging from 0 to 48 weeks in anti-PD-1 monotherapy. CONCLUSIONS:Our study shows rising reporting frequencies of endocrinopathies caused by ICIs, especially aggravated in combination therapy. Clinicians should be early aware of latent endocrine toxicity and different onset time of endocrinopathies when implementing ICI therapies.

SUBMITTER: Bai X

PROVIDER: S-EPMC7447663 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase.

Bai Xuefeng X Lin Xiahong X Zheng Kainan K Chen Xiaoyu X Wu Xiaohong X Huang Yinqiong Y Zhuang Yong Y

Endocrine 20200607 3

<h4>Purpose</h4>Our study aimed to map endocrine toxicity spectrum of immune checkpoint inhibitors (ICIs).<h4>Methods</h4>We obtained data from VigiBase, between January 1, 2011 and March 6, 2019. All endocrine adverse drug reactions (ADRs) were classified by group queries according to the Medical Dictionary for Regulatory Activities. Disproportionality analysis was performed with information component (IC) and reporting odds ratio (ROR). We used IC to identify meaningful endocrinopathies associ ...[more]

PMID: 32507965

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Project description:IntroductionIn the treatment of the individual patient, a vision is to achieve the best possible balance between benefit and harm. Such tailored therapy relies upon the identification and characterisation of risk factors for adverse drug reactions. Information relevant to risk factor considerations can be captured in adverse event reports and could be utilised in statistical signal detection.ObjectiveThe aim of this study was to explore whether statistical screening of a broad range of risk factors within a global database of adverse event reports could uncover signals of risk groups for adverse drug reactions.MethodsSubgroup disproportionality analysis was applied to 15.4 million reports entered in VigiBase, the World Health Organization (WHO) global database of individual case safety reports, up to August 2017. Disproportionality analyses for drug-adverse event pairs were performed (1) in the full database and (2) across a range of subgroups defined by the following covariates: patient age, sex, body mass index, pregnancy, underlying condition, reporting country, and geographical region. Drug-adverse event pairs disproportionately over-reported in such subgroups, but not in the full database, and with a substantial difference between the two observed-to-expected ratios, were highlighted as statistical signals. These were further prioritised, through filtering and sorting, for clinical assessment, whereafter clinically relevant signals were communicated to the pharmacovigilance community and the public.ResultsAssessments were performed for 354 prioritised statistical signals, resulting in seven communicated signals describing previously unrecognised potential risk groups related to age (elderly), sex (male and female), body mass index (underweight and obese), and geographical region (Asia), all except one for already established adverse drug reactions. Important aspects considered in the assessments included an evaluation of the disproportionate over-reporting in the subgroup by reviewing alternative explanations and reporting patterns for similar drugs/adverse events/subgroups, and a search for plausible mechanisms to support the risk hypothesis.ConclusionsThis study reveals that it is possible to uncover signals of risk groups for adverse drug reactions through incorporation of broad risk factor screening into statistical signal detection in a global database of adverse event reports. Our findings suggest the potential to use such statistical methodologies for risk characterisation in subpopulations of concern.

Project description:Introduction: The panorama of drug-induced ototoxicity has widened in the last decades; moreover, post-marketing data are necessary to gain a better insight on ototoxic adverse drug reactions (ADRs). The aim of this study was to perform an analysis of ADR reports describing drug-induced ototoxicity from the Italian spontaneous reporting system (SRS). Methods: As a measure of disproportionality, we calculated the reporting odds ratios (RORs) and 95% confidence intervals (CIs) with a case/non-case methodology. Cases were all suspected ADR reports regarding drug-induced ototoxicity collected into the Italian SRS from 2001 to 2017. Non-cases included all other ADRs reported in the same period. Results: Of 325,980 reports, 652 included at least one ototoxic ADR, compared with 325,328 non-cases. Statistically significant adjusted RORs were found for drugs for cardiovascular disorders, urologicals, teriparatide, amikacin, prulifloxacin, rifampicin and isoniazid, cisplatin, hormone antagonists, tacrolimus, pomalidomide, tramadol, and antidepressants. Significant adjusted RORs in relation to tinnitus were also observed for doxazosin (ROR 5.55, 95% CI 2.06-14.93), bisoprolol (4.28, 1.59-11.53), nebivolol (8.06, 3.32-19.56), ramipril (3.96, 2.17-7.23), irbesartan (19.60, 9.19-41.80), betamethasone (4.01, 1.28-12.52), moxifloxacin (4.56, 1.71-12.34), ethambutol (12.25, 3.89-38.57), efavirenz (16.82, 5.34-52.96), sofosbuvir/ledipasvir (5.95, 1.90-18.61), etoposide (7.09, 2.63-19.12), abatacept (6.51, 2.42-17.53), indometacin (6.30, 2.02-19.72), etoricoxib (5.00, 2.23-11.23), tapentadol (4.37, 1.09-17.62), and timolol combinations (23.29, 9.53-56.95). Moreover, significant adjusted RORs for hypoacusis regarded clarithromycin (3.95, 1.86-8.40), azithromycin (10.23, 5.03-20.79), vancomycin (6.72, 2.14-21.11), methotrexate (3.13, 1.00-9.81), pemetrexed (4.38, 1.40-13.76), vincristine (5.93, 1.88-18.70), vinorelbine (21.60, 8.83-52.82), paclitaxel (2.34, 1.03-5.30), rituximab (3.20, 1.19-8.63), interferon alfa-2b (17.44, 8.56-35.53), thalidomide (16.92, 6.92-41.38), and deferasirox (41.06, 20.07-84.01). Conclusions: This study is largely consistent with results from literature. Nevertheless, propafenone, antituberculars, hormone antagonists, teriparatide, tramadol, and pomalidomide are unknown for being ototoxic. Hypoacusis after the use of vinorelbine, methotrexate, and pemetrexed is unexpected, such as tinnitus related with etoposide, nebivolol, betamethasone, abatacept, sofosbuvir/ledipasvir, and tapentadol, but these considerations require further investigation to better define the risk due to the paucity of data. Moreover, physicians should be aware of the clinical significance of ototoxicity and be conscious about the importance of their contribution to spontaneous reporting.

Project description:Unlabelled: In recent years, immune checkpoint inhibitors have emerged as effective therapies for advanced neoplasias. As new checkpoint target blockers become available and additional tumor locations tested, their use is expected to increase within a short time. Immune-related adverse events (irAEs) affecting the endocrine system are among the most frequent and complex toxicities. Some may be life-threatening if not recognized; hence, appropriate guidance for oncologists is needed. Despite their high incidence, endocrine irAEs have not been fully described for all immunotherapy agents available. This article is a narrative review of endocrinopathies associated with cytotoxic T lymphocyte-associated antigen-4, blockade of programmed death receptor 1 and its ligand inhibitors, and their combination. Thyroid dysfunction is the most frequent irAE reported, and hypophysitis is characteristic of ipilimumab. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for clinical management are suggested. Heterogeneous terminology and lack of appropriate resolution criteria in clinical trials make adequate evaluation of endocrine AEs difficult. It is necessary to standardize definitions to contrast incidences and characterize toxicity patterns. To provide optimal care, a multidisciplinary team that includes endocrinology specialists is recommended.Implications for practiceImmune checkpoint inhibitors are already part of oncologists' therapeutic arsenal as effective therapies for otherwise untreatable neoplasias, such as metastatic melanoma or lung cancer. Their use is expected to increase exponentially in the near future as additional agents become available and their approval is extended to different tumor types. Adverse events affecting the endocrine system are among the most frequent and complex toxicities oncologists may face, and some may be life-threatening if not recognized. This study reviews endocrinopathies associated to immune checkpoint inhibitors available to date. Incidence, timing patterns, and clinical presentation are discussed, and practical recommendations for management are proposed.

Project description:BACKGROUND:Immune-checkpoint inhibitors (ICIs) emerged as a novel class of drugs for the treatment of a broad spectrum of malignancies. ICIs can produce durable antitumor responses but they are also associated with immune-related adverse events (irAEs). Endocrinopathies have reported as one of the most common irAEs of ICIs. METHODS:This study aimed to quantify association of endocrine adverse events (AEs) and ICI therapy and also to characterize the profiles of ICI-related endocrine complications from real-world practice. Data from the first quarter of 2014 to first quarter of 2019 in FDA Adverse Event Reporting System (FAERS) database were gathered to conduct disproportionality analysis. The definition of endocrine AEs relied on the preferred terms (PTs) provided by the Medical Dictionary for Regulatory Activities (MedDRA). Two signal indices based on statistical shrinkage transformation, reporting odds ratios (ROR) and information component (IC), were used to evaluate correlations between ICIs and endocrine events. For ROR, it was defined a signal if the lower limit of the 95% confidence interval (ROR025) more than one, with at least 3 cases. For IC, lower end of the 95% confidence interval of IC (IC025) exceeding zero was deemed statistically significant. RESULTS:A total of 29,294,336 records were involved, among these 6260 records related to endocrine AEs after ICIs treatment were identified. In general, male had a slightly lower reporting frequencies for ICIs-related endocrinopathies compared with female but not significant (ROR?=?0.98 95%CI: 0.93-1.04) and the difference varied in several common endocrine AEs. Notably, in general, ICI drugs were significantly associated with over-reporting frequencies of endocrine complications, corresponding to IC025?=?2.49 and ROR025?=?5.99. For monotherapy, three strategies (anti-PD-1, anti-PD-L1 and anti-CTLA-4) were all associated with significant increasing endocrine events. Different reporting frequencies emerged when anti-CTLA-4 therapy was compared with anti-PD-1/PD-L1 medications for endocrine toxicities, corresponding to ROR?=?1.68 (95%CI 1.55-1.83), ROR?=?2.54 (95%CI 2.20-2.93), respectively. Combination therapy was associated with higher risk of endocrinopathies compared with monotherapy (ROR?=?2.00, 95%CI 1.89-2.11). When further analysis, the spectrum of endocrine AEs differed in immunotherapy regimens. Hypothyroidism (N?=?885,14.14%), adrenal insufficiency(N?=?730,11.66%), hypophysitis (N?=?688,10.99%) and hyperthyroidism (N?=?472,7.54%) were top 4 ranked endocrine events after ICI therapy and their reporting frequency also differed in ICI immunotherapies. CONCLUSION:Our pharmacovigilance analysis shows a high reporting frequency of endocrine AEs provoked by ICI monotherapy (especially anti-CTLA-4 therapy) and further reinforced by combination therapy. In addition, treatment with different ICI immunotherapies may result in a unique and distinct profile of endocrinopathies. Early recognition and management of ICI-related endocrine irAEs is of vital importance in clinical practice.

Project description:Introduction:Developing countries can improve their pharmacovigilance systems by analysing their own medication safety data. Objective:The aims of this study were to characterize Uganda's reported adverse drug reaction (ADR) onsets in 2012-2015 that were registered on VigiBase® by 31 December 2017, to document delays in international visibility and the influence of covariates on this delay from ADR onsets in 2013 + 2014, to examine data quality, and to illustrate analytical approaches for safety data, particularly for patients receiving antiretroviral therapy (ART). Methods:International delay was defined as elapsed time from complete ADR onset date to entry date on VigiBase®, with covariates examined using Cox proportional hazards regression. Simple random sampling was used to locate the paper-based ADR forms for data quality assurance. Disproportionality for signal detection focused on serious singleton ADR onsets in patients receiving ART. Results:Uganda's VigiBase® had 1018 patient entries with complete ADR onset dates: 260 in 2012, 293 in 2013, 305 in 2014 and 160 in 2015. Only 16% (154/953) of ADR onsets in 2012-2015 were in patients aged?<?20 years for whom randomly sampled ADR forms were less fully completed; 87% (889/1018) comprised a singleton sign/symptom; half were serious. Median delay from ADR onset to international visibility was 11 months for ADR onsets in 2013?+?2014, and longest for healthcare professionals other than pharmacists and physicians. Disproportionality for serious ADR onsets in patients receiving ART included anaemia with zidovudine, renal impairment with tenofovir, Stevens-Johnson syndrome with nevirapine and skin rash with efavirenz. Conclusions:Barely one ADR onset per day was registered on VigiBase® from those submitted to Uganda's National Pharmacovigilance Centre during 2012-2014; only one in six was from patients aged?<?20 years. Paediatric pharmacovigilance requires more emphasis in Uganda. Delays from reported ADR onset to international visibility on VigiBase® need to reduce dramatically. Quality assurance revealed rectifiable data entry deficits. Signal detection performed well for patients receiving ART.

Dataset Information

Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase.

Publications

Mapping endocrine toxicity spectrum of immune checkpoint inhibitors: a disproportionality analysis using the WHO adverse drug reaction database, VigiBase.

Similar Datasets

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