Therapeutic Advances in Drug Safety最新文献

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, life-threatening lung disease with a global incidence of 0.09-1.30 per 10,000 individuals. Pirfenidone and nintedanib are the approved treatments for IPF.

Objectives: This study evaluated the real-world safety and tolerability profiles of pirfenidone and nintedanib in IPF patients treated at the Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS ISMETT). A comparative analysis was conducted based on the number, types, and severity of adverse drug reactions (ADRs) and to identify potential predictors of treatment discontinuation or ADR onset based on patient characteristics.

Design: A retrospective observational study was conducted on 531 IPF patients treated at IRCCS ISMETT with either pirfenidone or nintedanib.

Methods: Eligible patients were selected based on the logged monthly dispensations provided by the pharmacy service for both therapies. Covariates were extracted from electronic medical records (age, sex, body mass index, smoking history, comorbidities, forced vital capacity (FVC) %, diffusing capacity of the lung for carbon monoxide (DLCO) %, 6-minute walk test (6-MWT), polytherapy, oxygen therapy, drug switch, etc.). ADRs were categorized by severity and follow-up status, and further classified according to the Medical Dictionary for Regulatory Activities, specifying the Preferred Terms and the related System Organ Classes. Chi-square or Fisher's exact test was used for categorical variables, and univariate and multiple logistic regression identified potential risk factors for ADR onset. Backward Stepwise logistic regression (BSLR) was used to determine independent variables associated with ADR occurrence.

Results: The nintedanib group had more frequent ADRs related to gastrointestinal and hepatobiliary disorders, with nausea, diarrhea, anorexia, and weight loss as the most common. The pirfenidone group had more ADRs related to skin, nervous system, and vascular disorders, such as rash, nausea, dizziness, and blood pressure imbalances. Significant baseline differences between groups included age, smoking status, FVC (%), DLCO (%), and 6-MWT, with the nintedanib cohort showing worse baseline characteristics. A total of 450 ADRs were reported: 59.6% for nintedanib and 40.4% for pirfenidone. Independent variables that significantly increased the likelihood of experiencing ADR were drug change, treatment type, gender, and age.

Conclusion: Identifying ADR predictors is essential for personalizing treatment strategies. Both pirfenidone and nintedanib are crucial in managing IPF, highlighting the need for further research to optimize personalized therapies and patient outcomes.

Background: Task shifting and sharing have been proposed as strategies to address healthcare staffing shortages and improve patient outcomes. In emergency and intensive care medicine, pharmacist interventions have shown potential to reduce medication errors and improve care quality. However, the precise benefits of pharmacist support in therapeutic drug monitoring (TDM) for emergency center inpatients require further verification.

Objective: To determine the contribution of pharmacist support in entering blood drug concentration test orders to patient safety during anti-methicillin-resistant Staphylococcus aureus (MRSA) drug administration in the emergency and critical care center, and investigate the association between this support and the frequency of vancomycin-induced kidney injury.

Design: Single-center retrospective cohort study comparing outcomes 2 years before and 2 years after implementing pharmacist support for blood concentration test order entry.

Methods: Patients receiving intravenous vancomycin with blood concentrations measured at the emergency center were included. Propensity score matching was used to minimize confounding. The primary outcome was the change in frequency of vancomycin-induced kidney injury before and after pharmacist support implementation.

Results: Pharmacist support significantly reduced the frequency of vancomycin-induced kidney injury (from 6.5% to 0.0%, p = 0.043) and shortened time to first TDM implementation (p = 0.019) in the overall cohort. Similar significant reductions were observed in the propensity score matched cohort (from 11.9% to 0.0%, p = 0.013).

Conclusion: Pharmacist support in entering blood drug concentration test orders significantly reduced vancomycin-induced kidney injury frequency and shortened time to first TDM, enhancing patient safety during anti-MRSA medication administration in the emergency and critical care center. This task-shifting approach demonstrates clear benefits for patient care and physician workload.

Background: The efficient distribution of Direct Healthcare Professional Communications (DHPCs) is crucial for ensuring healthcare providers promptly receive important new safety information.

Objectives: This study aimed to evaluate the implementation of the electronic distribution of DHPCs by the Danish Medicines Agency (DKMA) and to assess how future safety communication can be improved.

Design: We conducted a web-based cross-sectional survey among Danish physicians using a self-administered questionnaire.

Methods: DKMA sends DHPCs to healthcare professionals via an electronic mailbox called e-Boks which is linked to the unique personal identifier. To evaluate DKMA's distribution of DHPCs, participants were asked about awareness, frequency and barriers of reading, preferred distribution channel and overall satisfaction. To further identify potential improvements, respondents were asked about general preferences regarding sender and channels of safety information in addition to which information sources they use to keep up-to-date.

Results: A total of 2238 physicians completed the survey corresponding to a response rate of 26% based on the total target population. The total awareness was 81%. Compared to previous research, awareness of GPs increased from 66% to 82%, and the percentage of GPs who rarely or never read DHPCs decreased from 33% to 20%. In addition, our study revealed a preference for receiving DHPCs electronically through e-Boks as opposed to workplace-delivered postal letters, and a preference for the DKMA over pharmaceutical companies as the sender of DHPCs. One-third of the respondents were either 'dissatisfied' or 'very dissatisfied' with the current solution. A professional mailbox and point-of-care alerts when prescribing may complement the primary distribution channel to strengthen the uptake. Additionally, existing information sources already frequented by the target group may be used to communicate safety information.

Conclusion: The DKMA's electronic distribution of DHPCs suggests an improvement and may serve as inspiration for other agencies. However, the considerable dissatisfaction calls for further improvements.

Background: Drug-drug interactions (DDI) are an important cause of adverse drug reactions (ADRs). Could large language models (LLMs) serve as valuable tools for pharmacovigilance specialists in detecting DDIs that lead to ADR notifications?

Objective: To compare the performance of three LLMs (ChatGPT, Gemini, and Claude) in detecting and explaining clinically significant DDIs that have led to an ADR.

Design: Observational cross-sectional study.

Methods: We used the French National Pharmacovigilance Database to randomly extract Individual Case Safety Reports (ICSRs) of ADRs with DDI (positive controls) and ICSRs of ADRs without DDI (negative controls) registered in 2022. Interaction cases were classified by difficulty level (level-1 DDI being the easiest and level-2 DDI being the most difficult). We give each LLM (ChatGPT, Gemini, and Claude) the same prompt and case summary. Sensitivity, specificity, and F-measure were calculated for each LLM in detecting DDIs in the case summaries.

Results: We assessed 82 ICSRs with DDIs and 22 ICSRs without DDIs. Among ICSRs with DDIs, 37 involved level-1 DDIs, and 45 involved level-2 DDIs. Correct responses were more frequent for level-1 DDIs than for level-2 DDIs. Regardless of difficulty level, ChatGPT detected 99% of DDI cases, and Claude and Gemini detected 95%. The percentage of correct answers to all DDI-related questions was 66% for ChatGPT, 68% for Claude, and 33% for Gemini. ChatGPT and Claude produced comparable results and outperformed Gemini (F-measure between 0.83 and 0.85 for ChatGPT and Claude and 0.63-0.68 for Gemini) to detect drugs involved in DDI. All exhibited low specificity (ChatGPT 0.68, Claude 0.64, and Gemini 0.36) and reported nonexistent DDIs for negative controls.

Conclusion: LLMs can detect DDIs leading to pharmacovigilance cases, but cannot reliably exclude DDIs in cases without interactions. Pharmacologists are crucial for assessing whether a DDI is implicated in an ADR.

Background: Fever is a common postoperative complication, typically caused by aseptic inflammation or infection. However, drug-induced fever (DIF) is an underdiagnosed etiology that should be considered in the differential diagnosis, especially in patients receiving complex medication regimens post-surgery.

Objectives: This systematic review aims to assess the current literature on DIF in post-surgical patients to improve diagnostic accuracy and patient care.

Design: Systematic review of case reports and case series.

Data sources and methods: This systematic review was conducted following the PRISMA 2020 guidelines. We included case reports and series involving post-surgical patients with fever linked to drug administration. Studies were retrieved from the PubMed, Scopus, Embase, and Web of Science databases, as well as gray literature sources. Quality and bias were assessed using the Joanna Briggs Institute (JBI) critical appraisal tools.

Results: A total of 16 studies (14 case reports and 2 case series) involving 23 patients were included. The most frequently implicated drugs were propofol, morphine, and cephalosporins. Fever onset ranged from immediate postoperative to several days later, with varied patterns, including intermittent, remittent, and continuous fever. The majority of patients recovered after drug discontinuation, although two cases resulted in death.

Conclusion: DIF is one of the causes of postoperative fever. Early identification and cessation of the offending drug are crucial for resolving the fever and preventing severe complications. Clinicians must remain vigilant in diagnosing DIF to improve patient outcomes post-surgery.

Background: Currently, the factors influencing small bowel bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs) remain unclear.

Objectives: This study aimed to assess NSAID-associated small bowel bleeding and evaluate the impact of other drugs on it through a pharmacovigilance study, thereby providing valuable insights for clinical practice.

Design: Data on NSAID-associated small bowel bleeding were retrospectively extracted from two public adverse drug reaction databases-the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) and the Japan Pharmaceuticals and Medical Devices Agency's Adverse Drug Event Reporting (JADER)-from 2004 to 2023 for further analysis.

Methods: The reporting odds ratio (ROR), a pharmacovigilance technique, was employed to identify signals of adverse reactions, and the Chi-square test was utilized to assess differences between groups.

Results: Multiple NSAIDs associated with small bowel bleeding were identified in both databases. In the drug combination analysis, no significant differences in the risk of small bowel bleeding were found between NSAIDs combined with proton pump inhibitors (PPIs) and NSAIDs alone in FAERS (all p > 0.05). Decreasing risks were found when multiple NSAIDs were combined with rebamipide or probiotics compared to NSAIDs alone in JADER (p < 0.05 and ROR  < 1). In subgroup analyses of age and sex, older adults and males who used aspirin showed higher risk signals in both databases (all p < 0.05 and ROR  > 1).

Conclusion: PPIs did not show a significant impact on NSAIDs-associated small bowel bleeding, while rebamipide and probiotics may exhibited a preventive effect against NSAIDs-associated small bowel bleeding. Older adults and males constituted risk factors for aspirin-associated small bowel bleeding.

Background: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are linked with immune-related adverse events (irAEs), including cardiac events.

Objective: This study aims to assess the reporting frequency of atrial fibrillation with ICIs using data from the Food and Drug Administration Adverse Event Reporting System (FAERS).

Design: It is an observational, retrospective, pharmacovigilance study.

Methods: Individual Case Safety Reports (ICSRs) were retrieved from FAERS up to September 24, 2024. Cases reporting one or more ICIs (atezolizumab, avelumab, cemiplimab, dostarlimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and tremelimumab) and atrial fibrillation were selected. Disproportionality analyses were performed by applying the reporting odds ratio (ROR) and the Informational Component (IC) with a 95% confidence interval (95% CI).

Results: A total of 1228 ICSRs were retrieved, of which 218 (17.75%) were related to combinations of ICIs. Most ICSRs (N = 812; 66.1%) referred to male patients and the age group most represented was ⩾65 years (N = 772; 62.9%). Atrial fibrillation was serious in 99.3% (N = 1220) of cases and had a fatal outcome (N = 248; 20.3%). Atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab were associated with a statistically significant higher reporting frequency of atrial fibrillation compared to all other drugs (ROR: 1.90, IC: 0.91; ROR: 1.94, IC: 0.92; ROR: 1.52, IC: 0.60; ROR: 1.30, IC: 0.38; ROR: 1.66, IC: 0.72, respectively). The anti-CTLA-4 ipilimumab showed a statistically significant lower reporting frequency of atrial fibrillation compared to all other drugs (ROR: 0.69, IC: -0.53) and to all other ICIs (ROR: 0.45, IC: -1.02). Moreover, anti-PD-L1 (ROR: 2.60, IC: 0.47) and anti-PD-1 (ROR: 2.12, IC: 0.16) were associated with a higher reporting of atrial fibrillation compared to anti-CTLA-4.

Conclusion: ICI-induced atrial fibrillation was serious and had severe outcomes. The anti-CTLA-4 showed a lower likelihood of reporting atrial fibrillation, while higher reporting was found with anti-PD-1 and anti-PD-L1. Further studies are needed to confirm this safety aspect.

Integrating real-world healthcare data is challenging due to diverse formats and terminologies, making standardization resource-intensive. While Common Data Models (CDMs) facilitate interoperability, they often cause information loss, exhibit semantic inconsistencies, and are labor-intensive to implement and update. We explore how generative artificial intelligence (GenAI), especially large language models (LLMs), could make CDMs obsolete in quantitative healthcare data analysis by interpreting natural language queries and generating code, enabling direct interaction with raw data. Knowledge graphs (KGs) standardize relationships and semantics across heterogeneous data, preserving integrity. This perspective review proposes a fourth generation of distributed data network analysis, building on previous generations categorized by their approach to data standardization and utilization. It emphasizes the potential of GenAI to overcome the limitations CDMs with GenAI-enabled access, KGs, and automatic code generation. A data commons may further enhance this capability, and KGs may well be needed to enable effective GenAI. Addressing privacy, security, and governance is critical; any new method must ensure protections comparable to CDM-based models. Our approach would aim to enable efficient, real-time analyses across diverse datasets and enhance patient safety. We recommend prioritizing research to assess how GenAI can transform quantitative healthcare data analysis by overcoming current limitations.

The increasing off-label use of medications needs a robust pharmacovigilance system. This is particularly crucial given the abundance of scientific data that can be harnessed to ensure a product's safety. Our review focuses on the off-label use of local anesthetics, a common practice in topical and intracameral applications. However, the occurrence of mydriasis, as indicated in the monographs/summaries of product characteristics, is an unexpected adverse event. Our aim is to provide a comprehensive understanding of mydriasis caused by local anesthetics, both as an unexpected adverse event and as an off-label use, to reinforce the importance of pharmacovigilance practices. We conducted a comprehensive search in Medline/PubMed and Google Scholar from two distinct perspectives: examining the occurrence of mydriasis with the use of local anesthetic as an adverse event and as an off-label use. Our search yielded 14 articles that reported mydriasis as an unexpected adverse event with the use of anesthetics, with dental procedures being a significant contributor to this type of event. Also, we identified eight articles that explored the off-label use of local anesthetics to induce mydriasis, with the most common method of drug administration being intracameral injection. These findings underscore the importance of our research in understanding the unexpected adverse event of mydriasis and the potential for off-label use of local anesthetics. They also highlight the need for continued involvement and vigilance in this area, as our understanding of these phenomena continues to evolve and further investigation is crucial. The use of local anesthetics for mydriasis holds significant promise, particularly in ophthalmological surgeries. This approach could potentially mitigate the adverse events associated with conventional mydriatics, offering a more efficient and safer alternative. Furthermore, using a single medication for akinesia, anesthesia, and mydriasis could significantly enhance the efficiency and convenience of surgical procedures. On the other hand, it is crucial to extend the knowledge of the mydriasis-anesthesia association through risk minimization activities (e.g., the inclusion of monographs/summary of product characteristics) to communicate the risk of mydriasis with the use of local anesthetics.