Therapeutic Advances in Drug Safety最新文献

Background: There has been notable progress in pharmacovigilance (PV) in low- and middle-income countries (LMIC) in the last decade. However, only a few of these PV systems are fully functional, unlike in high-income countries where stringent legislation, regulations and operational guidelines have enabled the establishment of effective PV systems. The key challenges faced in LMIC include organisational inefficiencies; weak infrastructure; inconsistent and poorly enforced regulations; and inadequate financing and shortage of trained personnel. Furthermore, low adverse event volume and poor data quality hinder the capacity for safety data generation and utilisation. With the increasing availability of essential and innovative medicines in LMIC, establishing robust PV systems is crucial for effective safety surveillance.

Objectives: This research aims to analyse the development of PV systems across high-, middle- and low-income countries and to carve out essential elements for functionality and sustainability of PV systems in LMIC.

Design: A convergent parallel mixed-methods design, combining qualitative and quantitative methods.

Methods: Qualitative and quantitative research consisted of semi-structured interviews and an online survey, respectively.

Results: Twelve key informants from 10 countries were interviewed and 52 respondents from 36 countries completed the online survey. From the qualitative and quantitative data, we identified nine essential elements for sustainable PV development in LMIC: understanding the drivers of PV development; adequately resolving core system challenges; implementing an efficient organisational structure and good governance; establishing procedures for PV activities; ensuring availability of qualified and trained staff; identifying alternate sources of financing; having a strategic development plan; adequately leveraging the health system; and effectively integrating the pharmaceutical sector in the national PV system.

Conclusion: Findings from this research indicate that significant efforts are still needed to upgrade PV systems in LMIC to meet global standards despite the progress achieved in recent years. Developing the different areas emerging from this research, within the framework of a holistic, fit-for-purpose PV system strengthening, would enable a comprehensive progression from basic to functional and thus sustainable PV systems in LMIC.

Background: Rational prescribing optimizes medicine use, reduces costs, and improves patient outcomes. However, adherence to rational prescribing practices varies, particularly in low- and middle-income countries like Ghana, where healthcare systems differ across urban, peri-urban, and rural settings.

Objectives: This study assessed adherence to WHO/INRUD prescribing indicators in public hospitals and determined each hospital's Index of Rational Drug Prescribing (IRDP).

Design: A retrospective descriptive study was conducted in 25 public hospitals across rural, peri-urban, and urban settings in the Ashanti Region of Ghana.

Methods: Data from 5091 patient encounters were analyzed to assess prescribing indicators, including the average number of medicines per encounter, generic prescribing, adherence to the Essential Medicines List (EML), antibiotic use, and injection prescribing. IRDP scores were calculated, and geographic comparisons were performed using analysis of variance (ANOVA), with p < 0.05 considered statistically significant.

Results: No hospital met the WHO target of <2 medicines per encounter (regional average: 3.63 ± 0.62). Generic prescribing averaged 72.26%, and EML adherence was 91.85%, with no hospital achieving 100%. Antibiotic prescribing exceeded the <30% target, averaging 60.84%. Injection use aligned best with WHO standards (average: 13.42%), with 22 of 25 hospitals meeting the <20% threshold. The regional IRDP was 3.67, with rural hospitals scoring lowest (3.63), followed by peri-urban (3.64) and urban hospitals (3.81). No significant geographic differences in IRDP scores were observed (p > 0.05).

Conclusion: While injection use aligns with WHO standards, gaps remain in generic prescribing, antibiotic use, and EML adherence. Strengthening prescriber training, antimicrobial stewardship programs, and policy enforcement is essential to improving prescribing practices and patient outcomes in public hospitals in the Ashanti Region.

Background: Chimeric antigen receptor T-cell (CAR-T) cell therapy represents a significant advancement in cancer treatment, offering remarkable responses in certain hematologic malignancies. However, the risk of secondary primary malignancies (SPMs) associated with CAR-T therapy is a growing concern. Recent studies suggest that antibiotics, which are frequently used in CAR-T patients, may influence this risk, yet their effects remain poorly understood.

Objective: This study aims to systematically evaluate the association between antibiotics and the incidence and timing of SPMs in patients receiving CAR-T cell therapy, using data from the FDA's Adverse Event Reporting System (FAERS) database.

Design: We analyzed reports from FAERS spanning from Q2 2017 to Q1 2024, focusing on SPMs associated with various CAR-T therapies.

Methods: A comprehensive signal analysis was conducted to explore the associations between antibiotic usage and specific SPMs for different CAR-T products. In addition, we employed cumulative hazard curves to evaluate the time to onset of SPMs in patients receiving antibiotics versus those who did not.

Results: We have provided a comprehensive summary of all signals for CAR-T-associated SPMs. In addition, our analysis identified significant variations in the association between antibiotics and SPM incidence depending on the CAR-T therapy administered. Antibiotics were associated with a decreased risk of SPMs in patients treated with anti-CD19 CAR-T therapies, particularly brexucabtagene autoleucel. Conversely, a higher risk of SPMs was observed in association with antibiotics for anti-BCMA therapies, with idecabtagene vicleucel showing a notably elevated risk. Notably, antibiotics were associated with an earlier onset of SPMs across CAR-T therapies, suggesting a possible relationship between antibiotics and the timing of these malignancies. Finally, we explored the underlying biological pathways that may be associated with these observations.

Conclusion: Antibiotics were associated with both the risk and timing of SPMs in patients undergoing CAR-T cell therapy. This study highlights the need for further research to better understand the complex interactions between antibiotics and CAR-T therapies, as well as the potential implications for clinical management and patient care.

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.