Therapeutic Advances in Drug Safety最新文献

Background: Blepharoptosis is one of the most common eyelid disorders in clinical ophthalmology. Previous evidence on drug-related blepharoptosis limited to case reports.

Objectives: This study aims to systematically evaluate the disproportionality signals of drugs associated with blepharoptosis using large-scale real-world data from the US FDA Adverse Event Reporting System (FAERS).

Design: A retrospective disproportionality analysis was conducted based on the FAERS database.

Methods: A total of 21,838,627 reports from the FAERS database, spanning 2004 to 2024, were included, with 19,541,994 reports retained after deduplication. Disproportionality analysis methods including reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker were employed to detect positive signals. The therapeutic purposes of the drugs, drug-related reporting patterns, drug signals strength, and onset times of adverse reactions were comprehensively assessed.

Results: A total of 9324 cases of blepharoptosis were confirmed, involving 20 identified with significant signals. They primarily include antineoplastic and immunomodulating agents, sensory organ drugs, and neuropsychiatric drugs. Eleven drugs had previously been reported to be associated with blepharoptosis, while 9 were newly identified. Botulinum toxin A, ravulizumab, and latanoprost were found to exhibit the strongest signals. Neuropsychiatric drugs (e.g., lidocaine) had a median onset time of 1-9 days, while antineoplastic and immunomodulating agents (e.g., ravulizumab) had a median onset time of 164-912 days. Avelumab and rosuvastatin showed stronger signals for elderly males, while botulinum toxin A and bupivacaine were more significant for younger females.

Conclusion: This study validates known associations such as immune checkpoint inhibitors and neuroregulatory agents, and identifies drug-related signals. There are significant differences in the onset times of adverse reactions across drug categories, suggesting the need for targeted monitoring.

Background: Emergency departments (EDs) provide urgent care to diverse patients. Medication-related tasks, crucial for safe diagnosis and treatment, often receive inadequate attention. Clinical pharmacists, experts in medication management, can improve outcomes and reduce costs.

Objectives: To investigate how the introduction of clinical pharmacists affects ED junior physicians' work-time distribution, with particular focus on medication-related tasks.

Design: A stepped-wedge design was employed, introducing pharmacists across three Norwegian EDs over a 9-month period, with each ED starting at staggered intervals.

Methods: Using the Work Observation Method By Activity Timing (WOMBAT) methodology, we observed junior physicians' activities in three EDs. The pharmacists were encouraged to adapt to the ED setting, integrate into the team, and identify ways to apply their expertise effectively. Medication reconciliation became their primary focus. We recorded 251 h of observation in the period without pharmacists present and 287 h in the intervention period, with pharmacists present. The proportion of time spent on different tasks was compared between the two periods.

Results: Junior physicians spent 81.0% of their work time on non-medication-related tasks, 11.6% on standby/movement, and 8.7% on medication-related tasks. There was no evidence that the overall time distribution was affected by the intervention. However, in ED2, the proportion of time spent on medication-related documentation was reduced from 6.1% to 2.5%, while standby time increased from 6.1% to 13% with pharmacists present. Face-to-face interactions with pharmacists accounted for less than 2% of the junior physicians' work time in all EDs.

Conclusion: In three Norwegian EDs, junior physicians' work time was predominantly spent on non-medication-related tasks, with only 8.7% dedicated to medication-related tasks. The introduction of clinical pharmacists did not significantly impact junior physicians' overall work-time distribution. Further research should investigate pharmacists' impact on ED care quality and efficiency.

Background: Considerable progress has been made in the estimation of drug safety treatment effects-particularly with observational medical claims and electronic medical record data. The use of the Target Trial framework, along with developments in statistical methodology such as doubly robust and G-estimation methods, has improved the ability to draw reliable causal inferences about drug and vaccine safety from observational data. However, such models rarely relate drug safety outcomes to other domains such as economic impacts. As shown by the COVID-19 pandemic, this is a significant limitation with potentially serious and long-term consequences.

Objective: The goal of this paper is to demonstrate that the availability of simulation tools would enable policy-makers to assess drug safety and effectiveness outcomes associated with alternative policies, as well as examine these effects in the context of other domains, such as economic outcomes.

Design: We develop an agent-based simulation model (ABM) of a peer navigator program to support engagement in HIV therapy in Tanzania. Results from the ABM are weighted to reflect the Tanzanian population and fed into the SPECTRUM model. This generates detailed demographic forecasts that are translated into macroeconomic impacts using labor force participation rates from the International Labor Organization, along with an econometric model of gross domestic product.

Results: The ABM simulation estimated that the peer navigation program increased ART participation for men and women by about 12%-15% with no strong trend over time. The impact on VLS, however, was cumulative and significant for both men and women. By year 3, VLS was improved by 33.9 percentage points for women and 32.6 percentage points for men. However, the overall impact of these estimates on mortality was modest-ranging from less than 500 lives per year at the start of the forecast period to about 2500 lives per year in 2030. Consequently, the associated macroeconomic impacts were also small. The relatively modest impacts were due to the limited opportunity for HIV control in Tanzania, which had already met its 95/95/95 goals.

Conclusion: Although the simulated macroeconomic effects of the peer navigator program in Tanzania were modest, the paper demonstrates the feasibility of linking behavioral ABM simulations of program impacts to subsequent demographic effects and, finally, macroeconomic performance. Moreover, given the clinical response in ART and VLS in the exposed population in Tanzania, it is likely that the same peer navigator intervention conducted in another country with a larger at-risk HIV population would be much larger.

Background: Dexmedetomidine may expedite recovery from acute kidney injury (AKI) in critically ill adults.

Methods: This study utilizes data from the fourth edition of the Medical Information Mart for Intensive Care (MIMIC-IV). Adult patients admitted to Beth Israel Deaconess Medical Center in Boston, Massachusetts, between 2008 and 2019 with AKI and who have at least two serum creatinine values recorded in the MIMIC-IV database meet study inclusion criteria. The primary outcome measure is the time (days) from diagnosis of AKI to recovery. Secondary outcome measures are hospital and ICU length of stay (LOS) as well as in-hospital mortality.

Results: A total of 1893 patients are included in this study. While 293 patients received dexmedetomidine, 1600 patients did not receive dexmedetomidine. Treatment with dexmedetomidine is associated with a 53.7% (95% CI: 46.8%-59.8%) decrease in the risk of recovery from AKI, on average, and this value is statistically significant (p < 0.001). Sensitivity analysis utilizing Cox regression of dexmedetomidine rate on time to AKI recovery demonstrated the opposite effect, however, with an adjusted HR of 1.42 (95% CI: 1.24-1.63, p value <0.001). Theories for this opposite effect are explored in the Discussion section of the manuscript. For patients who receive dexmedetomidine, hospital and ICU LOS, on average, increase by 18.98% and 32.56%, respectively (p value <0.001). Patients who receive dexmedetomidine have 0.6 times the odds of in-hospital mortality, on average, compared to patients who do not receive dexmedetomidine, which is statistically significant (p value 0.006).

Conclusion: Dexmedetomidine may be associated with slower recovery from AKI in critically ill adults. The prolonged hospital and ICU LOS associated with dexmedetomidine may be related to reduced mortality, but these results require additional investigation. These exploratory results warrant further investigation to better understand the clinical implications of dexmedetomidine exposure in the setting of AKI.

Background: Cholangiocarcinoma (CCA) is a cancer with a low survival rate. New drugs targeting molecular alterations, oncogenic mutations, and gene fusions are being tested as second-line treatments.

Objectives: This systematic review aims to summarize the results obtained with three new targeted therapies-pemigatinib, futibatinib, and ivosidenib-for the treatment of CCA, evaluating their safety and tolerability profiles in patients, compared to current standard therapies.

Data sources and methods: A systematic literature search was performed with a cutoff date of July 24, 2023, in MEDLINE, Embase, and the Cochrane Library. The authors also conducted an advanced search in the ClinicalTrials.gov database, evaluated conference abstracts, article bibliographies, and drug monographs. Studies involving the treatment of patients with pemigatinib, futibatinib, and ivosidenib were considered. The selected studies had to report adverse events (AEs) that occurred during treatment with these therapies.

Results: The most common AEs observed with pemigatinib, futibatinib, and ivosidenib were alopecia, diarrhea, fatigue, and dysgeusia. In addition, hyperphosphatemia, hypophosphatemia, and ocular disorders were observed with fibroblast growth factor receptor (FGFR) inhibitors, while the isocitrate dehydrogenase 1 (IDH1) inhibitor was associated with dose-dependent prolongation of the corrected QT interval (QTc). These AEs were effectively managed through dose adjustments.

Conclusion: FGFR2 and IDH1 inhibitors have good tolerability in the population examined. All AEs were optimally managed with dose modulation. Future studies should focus on identifying the most effective dosages to further enhance treatment safety.

Background: Pharmacovigilance (PV) inspections are critical regulatory assessments that evaluate the robustness and compliance of a company's drug safety system. Despite their significance, there is limited published guidance on how organizations-particularly Medical Safety functions-can prepare operationally for such inspections.

Objectives: To share practical, experience-based insights and organizational strategies for inspection readiness, execution, and follow-up, based on a recent large-scale European Medicines Agency PV inspection.

Design: Descriptive case-based manuscript outlining the stepwise activities undertaken before, during, and after a regulatory PV inspection, with a focus on Medical Safety coordination.

Methods: An internally coordinated approach was implemented, including preparatory meetings, document request management, cross-functional mock inspections, role assignments, and communication planning. A structured system was established for Medical Safety responses involving on-site and remote collaboration among safety leaders.

Results: The inspection was successfully completed. The coordinated system enabled timely, consistent, and quality-controlled responses. Visual tools, including timelines and workflows, supported operational efficiency and stakeholder alignment. Post-inspection debriefs further informed process improvements across Medical Safety functions.

Conclusion: This manuscript provides a practical, case-based framework for PV teams to approach regulatory inspections with strategic foresight and cross-functional coordination. The experience shared can serve as a useful reference, particularly for Medical Safety professionals and organizations seeking to strengthen inspection readiness and compliance operations.

Background: Statins have been demonstrated to decrease cardiovascular events in high-risk patients. Statin-induced myotoxicity is a major contributor to statin intolerance and often the leading cause of statin discontinuation. Studies on the association between statin use and rhabdomyolysis risk remain limited.

Objectives: This study aimed to compare the risk of rhabdomyolysis in patients who used statins versus those who did not.

Design: A population-based case-control study was conducted.

Methods: Data were collected from the Taiwan National Health Insurance Research Database between 2011 and 2020, involving 186,604 individuals with rhabdomyolysis and 746,416 without. Each patient with rhabdomyolysis (case group) was matched with four control patients based on the index year. Statins were assessed in both groups.

Results: Approximately 50% of study participants were male, with an average age of 53 years. After confounding variables were adjusted for, patients who used statins exhibited a higher risk of rhabdomyolysis than those who did not (adjusted odds ratio (OR): 1.70, 95% confidence interval (CI): 1.68-1.73). Psychiatric disorders, alcoholism, generalized epileptic seizure, heat stroke, and crush injury were independent risk factors of rhabdomyolysis. Patients with psychiatric disorders who used statins exhibited a substantial risk of rhabdomyolysis (adjusted OR: 2.30, 95% CI: 1.95-2.71) compared with the reference group of patients without psychiatric disorders who did not use statins.

Conclusion: Statin use was associated with a higher risk of rhabdomyolysis, and patients with psychiatric disorders who used statins exhibited an additive risk of rhabdomyolysis. These findings emphasize the need for clinicians to remain attentive to the potential risk of rhabdomyolysis in patients prescribed statins, especially in those with psychiatric disorders. Proactive monitoring, early recognition of symptoms, and individualized risk-benefit assessments are crucial to optimize treatment outcomes while minimizing adverse effects.

Background: Deregulated Notch signaling is implicated in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed or refractory NHL or CLL.

Objectives: This phase I clinical trial assessed the safety and efficacy of crenigacestat in patients with relapsed or refractory NHL and CLL. The main objectives were to characterize the safety profile, to confirm the recommended phase II dose of crenigacestat in patients with hematological malignancies, and to assess preliminary antitumor activity.

Design: A phase I trial enrolling patients with relapsed or refractory NHL and CLL, with Notch tumor alteration based on molecular or immunohistochemistry tumor pre-screening.

Methods: Eligible patients received crenigacestat 50 mg orally three times per week, for a 28-day cycle, until disease progression or unacceptable toxicity. Tumor responses were assessed using the Revised Response Criteria for Malignant Lymphoma and the National Cancer Institute Working Group for CLL.

Results: Overall, 62 patients (40 with NHL and 22 with CLL) were pre-screened for a Notch alteration. Notch alteration was identified in 21/62 (34%) of patients pre-screened. Nine patients (five with peripheral T-cell NHL and three with CLL) with Notch alteration were eligible for the clinical trial and treated. The most common adverse events in all grades of severity were diarrhea (56%), nausea (56%), platelet count decrease (44%), and fatigue (33%). One patient (11%) with peripheral T-cell lymphoma obtained a partial response.

Conclusion: Crenigacestat demonstrated a modest clinical activity at the recommended dose in adult patients with relapsed or refractory NHL or CLL.

Trial registration: NCT01695005.

Artificial intelligence (AI) has rapidly evolved from experimental applications in pharmacovigilance (PV) to being considered for routine use. This review critically examines AI's potential to revolutionize drug safety monitoring, focusing on practical implementation challenges such as ensuring AI's consistent and transparent performance, reducing multiple sources of bias, and addressing interpretability issues. It emphasizes the transition from experimental use to a routine, scalable capability within PV. It examines AI's evidence base in specific applications, its ability to enhance actionable insights, and how organizations can safeguard against unintended consequences in multi-AI system environments. These considerations are vital as AI moves from theory to practice in PV.

Background: Drug-related problems are common in older individuals. A medication reconciliation has the goal of identifying and maintaining an accurate medication list and can serve to prevent drug-related problems caused by discrepancies.

Objectives: This study aimed to explore primary care physicians' intentions towards performing medication reconciliation in patients with multimorbidity using a theory-based questionnaire.

Design: A survey study was conducted from February to March 2024.

Methods: An anonymous web-based questionnaire was developed, validated and distributed to 674 primary care physicians in southern Sweden. The questionnaire targeted attitudes, perceived norms, perceived behavioural control and generalised intentions towards performing a medication reconciliation, constructs derived from the theory of planned behaviour and the reasoned action approach theory. Outcome measures were overall scores for predictors, and the correlation between predictors and intentions towards performing a medication reconciliation was analysed using a multiple linear regression model.

Results: With 206 surveys answered, the response rate was 31%. We found items targeting attitudes to have the highest overall mean score on a seven-point Likert scale (6.42), followed by generalised intention (6.17), subjective norms (5.45) and perceived behavioural control (5.15). Women had significantly higher scores for attitudes (p-value 0.001), subjective norms (p-value 0.050) and generalised intention (p-value 0.001). Groups with more than 10 years of work experience had significantly higher overall mean scores for perceived behavioural control (p-value 0.043). The correlation between predictors and generalised intention found attitudes and perceived behavioural control to be significant predictors of intentions to perform medication reconciliation in multimorbid older individuals (p-value < 0.001).

Conclusion: We found attitudes and perceived behavioural control to be significant predictors of primary care physicians' intention to perform a medication reconciliation in patients with multimorbidity. These findings provide important insights into how future interventions targeting behavioural predictors can be developed.