Expert Opinion on Drug Safety最新文献

Background: Immune checkpoint inhibitors (ICIs)-associated cardiotoxic events (CEs) are of increasing concern. Existing research about glucocorticoids (GCs) on immunotherapy focused on ICIs' efficacy and patients' outcome. The influence of GCs on ICIs-associated CEs and myocardial damage (MD) remains unknown.

Research design and methods: This single-center retrospective study included patients treated with ICIs from 2018 to 2022, with follow-up period ending on 30 June 2023. The incidence, risk factors of ICIs-associated CEs, especially MD were described. Additionally, the impact of baseline GCs was assessed by propensity score matching (PSM) to mitigate intergroup differences and ensure comparability.

Results: Among 1018 patients, 204 (20.04%) experienced ICIs-associated CEs, including 71 (6.97%) with MD. The mean follow-up time was 40.39 (95% CI 38.47-42.31) weeks. The median time to onset of MD was the shortest at 12.57 weeks (IQR 5.29-25.14). Tumor type, co-medication with platinum and angiogenesis inhibitors may be influential factors of MD. After PSM, the relative risks of CEs (OR 0.4625,95%CI 0.2514-0.7235, p = 0.0020) and MD (OR 0.3254, 95% CI 0.1190-0.8898, p = 0.0378) in GCs1 ≥ 20 mg group were both significantly lower than those in GCs1 < 20 mg.

Conclusion: GCs ≥ 20 mg during the first ICIs treatment cycle is significantly associated with the reduced risks of both ICIs-associated CEs and MD.

Background: Alzheimer's disease (AD) is the most common form of dementia. The combination of Donepezil and Memantine is the only FDA-approved therapy for AD, but its adverse drug reactions (ADRs) lack systematic analysis. This study carried out drug combination analysis for AD population to provide evidence support for clinical safety of drug use.

Research design and methods: Using FAERS database reports (January 2004-January 2024) with Donepezil and Memantine as primary suspected drugs, four disproportionality analysis methods - ROR, PRR, BCPNN, and EBGM - were applied to identify positive ADR signals. Subgroup analyses were conducted by age and gender.

Results: A total of 712 reports were analyzed (54.6% female, 55.1% aged 65-85). Across the AD population, 42 ADRs were identified, including hypertensive crisis, hyperglycemia, hyperosmolar nonketotic syndrome, proteinuria, and hydronephrosis, many of which were newly reported. Subgroup analysis revealed prostate hypertrophy, acute kidney injury, and cerebral infarction in males, while females experienced more severe cardiovascular events, such as complete AV block and ventricular extrasystole. Additional ADRs included hyperkalemia, sinus bradycardia, and extrapyramidal disorders.

Conclusions: Despite partial consistency of combined ADRs for Donepezil and Memantine with instructions, new ADR signals emerged, with significant differences in AD subgroups.

Background: Cell-cycle protein-dependent kinase 4 and 6 inhibitors (CDK4/6is) in combination with endocrine therapy (ET) are widely used in patients with early and advanced breast cancer (BC). CDK4/6is also lead to numerous side effects. This study aims to elucidate the relationship between CDK4/6is and hepatotoxicities.

Research design and methods: As of 31 March 2024, we conducted a systematic search of PubMed, Embase, and the Cochrane Library databases, as well as several oncology conference proceedings. We included 20 randomized controlled trials (RCTs) with 24,342 breast cancer (BC) patients and 400 cases from the FDA Adverse Event Reporting System (FAERS). Fixed-effect and random-effect models were used to calculate odds ratios (ORs) of hepatotoxicity in the RCTs, while Reporting Odds Ratios (RORs) were calculated for the FAERS data.

Results: Overall, CDK4/6 inhibitors (CDK4/6is) were associated with significant hepatotoxicities compared to controls (OR = 1.76, 95%CI 1.40-2.22, I² = 75%). Palbociclib, ribociclib, and abemaciclib exhibited significant hepatotoxicities, while dalpiciclib did not. FAERS data showed significant liver enzyme and organ toxicity signals for ribociclib and abemaciclib but not for palbociclib.

Conclusions: CDK4/6is increase the risk of hepatotoxicities in patients with BC. Palbociclib, ribociclib, and abemaciclib caused liver damage, while dalpiciclib did not. The most common manifestations were elevated ALT and AST levels.

Introduction: BACE1 (beta-site amyloid precursor protein cleaving enzyme 1) inhibitors have shown promise in treating Alzheimer's disease (AD) by reducing amyloid-beta (Aβ) production. However, clinical trials of inhibitors such as atabecestat, verubecestat, and lanabecestat have faced challenges, including limited efficacy and significant adverse effects.

Areas covered: This narrative review discusses randomized-controlled trials of BACE1 inhibitors. Literature searches were conducted using PubMed and Web of Science for studies from 2010 to 2024. Association with BACE1's widespread expression beyond the brain shows adverse effects such as anxiety, depressive symptoms, and hepatotoxicity.

Expert opinion: The trial results underscore the need for CNS-specific BACE1 inhibitors to reduce adverse effects. Future research should focus on optimizing drug design and identifying additional therapeutic avenues, such as prostate cancer and insulin resistance.

Introduction: This research evaluated the association between glucagon-like peptide-1 receptor agonists (GLP-1 RA) and bowel obstruction or ileus.

Methods: We searched databases, including Medline, Embase, and Cochrane, for studies on adult patients treated with GLP-1 RA. We included randomized control trials (RCT), cohort, case-control studies, and case reports. We used the Cochrane Risk of Bias tool to evaluate the quality of RCTs and the Newcastle-Ottawa Scale for cohort and case-control studies.

Results: Out of 317 records identified, 14 studies were included in the systematic review. The meta-analysis included 6 studies with a combined total of 550,426 participants. The use of GLP-1 RA did not show an incremental risk of bowel obstruction or ileus compared to controls (OR 1.95, 95% CI 0.43-8.79). However, the studies had high heterogeneity (I² = 94%). A subgroup analysis by specific medication revealed that liraglutide was associated with a significantly high risk of bowel obstruction or ileus (OR 3.0, 95% CI 2.03-4.45; I² = 0%).

Conclusions: GLP-1 receptor agonists do not significantly increase the risk of bowel obstruction or ileus. However, liraglutide is associated with a higher risk compared to semaglutide. Clinicians should remain aware of these rare events while recognizing the benefits of GLP-1 receptor agonists for glycemic control and cardiovascular health.

Prospero registration: CRD42024585971.

Introduction: Antibody-drug conjugates (ADCs) have radically transformed the therapeutic landscape for cancer treatment, but little is known about the treatment-related fatal adverse events (FAEs). We aimed to comprehensively investigate the safety of ADCs regarding treatment-related FAEs.

Methods: We conducted a systematic search of PubMed, Embase, and the Cochrane database for randomized controlled trials (RCTs) of ADCs. The meta-analysis assessed the incidence of treatment-related FAEs and the odds ratio (OR) in the ADCs group compared with the control group.

Results: A total of 49 RCTs involving 13,052 patients treated with ADCs were included. The incidence of treatment-related FAEs in the ADCs group was 0.62% (95% CI = 0.36-1.08), while the control group was 0.52% (95% CI = 0.29-0.95), with an OR of 1.41 (95% CI = 1.12-1.79; p < 0.05). In the subgroup analysis by drug and cancer type, gemtuzumab ozogamicin, which for acute myeloid leukemia were associated with a higher risk of treatment-related FAEs compared to controls (OR = 1.63; 95% CI = 1.12-2.36; p < 0.05). There was no evidence of publication bias observed.

Conclusions: The meta-analysis of RCTs found that ADCs were associated with an increased risk of treatment-related FAEs compared with the control group. Moreover, the occurrence of treatment-related FAEs was associated with specific types of ADCs.

Background: The safety profile of CDK4/6 inhibitors has not yet been systemically analysed in the real world. This study aimed to provide a comprehensive understanding of AEs associated with CDK4/6 inhibitors using the FAERS database.

Methods: FAERS data (2014Q1 to 2022Q4) were searched for reports of all FDA-approved CDK4/6 inhibitors across all indications. We used the SMQ generalized search AEs on the PT level. Disproportionality analysis was used to detect safety signals by calculating RORs.

Results: Within the standardized MedDRA queries, significant safety signals were found, including those for palbociclib [haematopoietic leukopenia, erythropenia], ribociclib [haematopoietic leukopenia , conduction defects], and abemaciclib [eosinophilic pneumonia, dehydration]. For AEs at the PT level, we found several significant blood and lymphatic system disorders for both palbociclib and ribociclib, such as abnormal full blood count and decreased white blood cell count for palbociclib and anisocytosis, neutropenia for ribociclib. Palbociclib also had high RORs for pseudocirrhosis, stomatitis, oral pain, and alopecia, while ribociclib had high RORs for electrocardiogram PR shortened, sinus arrhythmia, and blood bilirubin abnormal. However, the RORs were significant for abemaciclib in terms of diarrhoea, vena cava thrombosis, thrombophlebitis migrans and pneumonitis.

Conclusion: CDK4/6 inhibitors differed in their safety profile reports.

Background: Riociguat is a novel soluble guanylate cyclase stimulator approved for the treatment of pulmonary arterial hypertension (PAH). Despite its widespread use, there has been a lack of large-scale studies assessing the adverse events (AEs) associated with this medication.

Research design and methods: This study aimed to evaluate the AEs related to Riociguat by analyzing data from the FDA Adverse Event Reporting System (FAERS) from Q4 2013 to Q1 2024. A total of 12,149 AE reports were analyzed using four different disproportionality signal detection methodologies to identify significant AEs associated with Riociguat.

Results: The analysis revealed 117 preferred terms (PTs) with significant disproportionality signals across all four methods. Among these, common AEs included 'headache,' 'dizziness,' 'hypotension,' 'nausea,' 'fall,' and 'loss of consciousness.' Notably, several unexpected AEs, such as 'fatigue,' 'malaise,' 'asthenia,' 'feeling abnormal,' and 'pain in extremity,' were identified, which were not highlighted in the product's package insert. Additionally, gender-specific differences were observed in certain adverse events.

Conclusions: This study offers insights into Riociguat's side effects. Clinicians should monitor patients closely for unexpected symptoms like limb pain and fatigue, paying particular attention to male patients, as some AEs occur more frequently in this group.

Background: Previous studies have explored the association between levetiracetam (LEV) and severe cutaneous adverse reactions (SCARs). However, most investigations have relied on clinical trial data or case reports from individual medical centers. Consequently, the precise relationship between LEV and SCARs in real-world settings remains elusive.

Research design and methods: Data from the FDA Adverse Event Reporting System (FAERS) and EudraVigilance databases were analyzed, focusing on LEV-associated SCAR events utilizing disproportionality analysis methods.

Results: This study identified a significant correlation between LEV and SCARs (p < 0.05). However, combined analyses with other antiepileptic drugs revealed that the association of LEV with SCARs was comparatively weaker (p < 0.05). Univariate logistic regression analysis indicated that males, individuals aged 45 ~ 65 years, and combination therapy with eslicarbazepine, phenytoin, carbamazepine, and lamotrigine significantly increased the risk of developing SCARs (p < 0.05). Notably, SCARs were most likely to occur within the initial week of LEV treatment (39.39%).

Conclusions: Despite certain limitations, this study offers updated insights into the association between LEV and SCARs. These findings underscore the significance of monitoring and actively managing LEV-associated SCARs to promote its safe and effective use.

Background: Cangrelor is used to reduce thrombotic events in adults undergoing percutaneous coronary intervention, but real-world safety data is limited. This study analyzes adverse events (AEs) related to cangrelor using the FDA adverse event reporting system (FAERS) database.

Methods: We employed statistical techniques such as the reporting odds ratio, proportional reporting ratio, bayesian confidence propagation neural network, and multi-item gamma poisson shrinker to analyze the data from the FAERS database.

Results: Out of a total of 15,011,506 case reports, 209 events were related to cangrelor. Thirty-one preferred term (PT) describing AEs were identified, affecting eight organ systems. The most reported PT was off-label use (n = 163). Several unexpected AEs not listed in the drug labeling emerged, including cardiac arrest, and cardiac failure. Although percutaneous coronary intervention was the most common indication (35.4%), numerous events were associated with off-label use, particularly for conditions such as acute myocardial infarction, antiplatelet therapy, and anticoagulant therapy.

Conclusion: Our research reveals both anticipated and unexpected AEs, providing important new information on the safety profile of cangrelor. Furthermore, we have discovered certain problems pertaining to product applications. It is recommended that manufacturers clearly highlight indications and usage instructions, and medical personnel closely follow drug administration protocols.