Therapeutic Advances in Drug Safety最新文献

As per Good Pharmacovigilance Practices, pharmaceutical companies must act on potential adverse reactions to drugs. With significant increases in the number of case reports in recent years, they face pressure to raise the efficiency of their processes while maintaining data integrity and patient safety. The use of Large Language Models (LLMs) in safety case intake provides potential to advance processes without compromising quality. In this perspective review, we highlight the potential benefits of LLMs in case intake workflows, and points to consider relating to the current research landscape, inspired by our proof-of-concept (PoC) study. Benefits include raising the consistency of data extraction, reducing bias, and enhancing efficiency. We reflect on challenges in realizing the potential of this new technology from a practical industry perspective, namely (a) measuring the Return on Investment, (b) early involvement of subject matter experts, (c) handling unclear regulatory expectations, (d) system integration, and (e) organizational readiness. We illustrate the potential and its challenges through the lens of our PoC's insights as well as through insights from published literature, which allowed us to estimate an efficiency gain from a business process perspective for data extraction and initial case report, demonstrating the technology's potential and practical applicability in real-world scenarios.

Background: Drug recalls safeguard patients from potentially harmful existing pharmaceutical products in the market due to safety concerns or manufacturing issues.

Objective: To analyze the drug recall patterns, frequencies, and causes based on the publicly available data from the Nepalese Drug Regulatory Authority, Department of Drug Administration (DDA).

Design: A 2-year retrospective secondary analysis was conducted based on drug recalls in Nepal, which is available from the official website of DDA, Nepal.

Methods: The substandard drug recalls data from April 17th, 2023 to May 14th, 2025 were included in the study from which information were extracted across various domains, including the drug name, dosage forms, manufacturing and expiry date, reasons for the recall, and recall date whereas, inclusion of falsified medicines and information regarding the "special permission," "news & updates," and "notices" sections within the DDA website were excluded from the studies to ensure only drug recalls were incorporated.

Results: The study showed that 50 recalls were made over the 2 year period. The majority of the recalled drugs were antibiotics (16%). The most common reasons for drug recalls were assay failure (34%) and non-compliance with standards set out by the Indian Pharmacopoeia-2022 (40%), followed by United States Pharmacopoeia-2022 (28%). Oral formulations (74%) were most commonly recalled, out of which tablets (32%), suspensions (16%), and syrups (12%) were recalled in greater frequencies among all the recall notices. Most recalls were made from domestic pharmaceutical companies (84%). The majority of the drugs (34%) were recalled after 15 months of the finished product being in the market, whereas only 26% were recalled within the first 5 months.

Conclusion: A robust and continuous evaluation of drug recalls by regulatory authorities can help reduce their frequency, lessen their impact on the healthcare system, and improve overall drug safety.

Background: Off-label prescribing represents an important aspect of clinical practice globally. However, there are limited data on the extent, evidence base and guideline support of off-label indications among the World Health Organization's essential medicines list (WHO EML), which serves as a cornerstone for healthcare systems, especially in low- and middle-income countries.

Objectives: This study aimed to systematically analyse the prevalence, therapeutic distribution, quality of evidence and inclusion in clinical guidelines of off-label uses for drugs listed in the 2023 WHO EML.

Methods: We conducted a descriptive analysis of all medications on the WHO EML using UpToDate^® Lexidrug™ database. For each medication, we extracted FDA-approved indications, identified off-label indications, the level of evidence supporting each off-label use (Level A, B, C, or G) and inclusion status in clinical practice guidelines. Off-label indications were categorized across 24 therapeutic systems, and system-to-system transitions from labelled to off-label uses were mapped.

Design: Descriptive cross-sectional observational study using a structured database analysis.

Results: Off-label prevalence among the WHO EML was 60.0%. The most frequent off-label use was observed in infectious diseases (30.5%) and oncology (25.2%). Most off-label uses were supported by Level C (32%) and Level B (30%) evidence, while only 11% were backed by Level A evidence. Notably, 64% of off-label uses were included in clinical guidelines, though many lacked associated evidence levels in Lexicomp. The majority of off-label uses remained within the same therapeutic system, with limited cross-system transitions.

Conclusion: This first comprehensive analysis of off-label uses across the WHO EML demonstrates widespread repurposing of essential medicines with variable evidence quality.

Background: Enzalutamide, approved in China for the treatment of prostate cancer (PC), has been studied for risk of seizure, but there is limited real-world evidence on this risk in China. Cases of posterior reversible encephalopathy syndrome (PRES) among enzalutamide-treated patients have been reported.

Objectives: To evaluate the risk of seizure and PRES in patients with PC treated with enzalutamide in China.

Design: Observational cohort study.

Methods: Data were extracted from electronic medical records of patients with PC aged ⩾18 years treated at three clinical sites in China who started enzalutamide between March 1, 2020 and May 31, 2022. The primary objective was to estimate the proportion (%) of enzalutamide- or alternative antiandrogen-treated patients who experienced seizure. The index date was the date of the start of treatment. The follow-up period started from the index date and included both on- and off-treatment periods.

Results: Demographic and clinical characteristics were generally similar between the enzalutamide (n = 385) and alternative antiandrogen (n = 365) groups. Risk factors for seizure were noted in 148 (38.4%) enzalutamide- and 130 (35.6%) alternative antiandrogen-treated patients. Median follow-up was 85 days for patients on enzalutamide and 196 days for those on alternative antiandrogens. During the on-treatment period, no patients on enzalutamide experienced seizure (95% confidence interval (CI): 0.00, 0.95), while one patient on an alternative antiandrogen experienced seizure (0.27%; 95% CI: 0.01, 1.48). The seizure incidence rates per 100 person-years for enzalutamide were 0.00 (95% CI: 0.00, 3.50) for the on-treatment period and 0.00 (95% CI: 0.00, 2.74) for the full follow-up period; for alternative antiandrogens, they were 0.58 (95% CI: 0.00, 2.14) during the on-treatment period and 0.43 (95% CI: 0.00, 1.61) during the full follow-up period. No cases of PRES were reported.

Conclusion: Among patients with PC in China, the risk of seizure was low in both the enzalutamide and alternative antiandrogen groups, despite the presence of risk factors for seizure in over one-third of patients.

Background: Methotrexate (MTX) is commonly prescribed for pediatric inflammatory diseases. However, clinical data on MTX-induced liver injury in children with rare inflammatory diseases currently remain limited.

Objectives: To examine the association between MTX treatment and abnormal liver function in children with inflammatory diseases and to characterize the clinical course of suspected MTX-induced liver injury cases.

Design: A self-controlled case series analysis.

Methods: This study was conducted on children aged <15 years with juvenile idiopathic arthritis, psoriasis, or inflammatory bowel disease between April 2016 and March 2024. Data were obtained from the Pediatric Medical Information Collection System database, which integrates electronic medical records from over 40 pediatric medical institutions in Japan. The risk period was defined as the 7-day interval following MTX administration. In addition, this analysis compared the incidence of outcomes during the risk period with the baseline period within the same individuals. The outcome was alanine aminotransferase (ALT) elevation, defined as serum ALT levels exceeding three times the upper limit of normal. The age-adjusted incidence rate ratio (aIRR) was calculated, and clinical courses were assessed following ALT elevation.

Results: Among 3696 children with inflammatory diseases, 587 received MTX treatment, while 81 developed abnormal ALT elevation. An increased risk of ALT elevation was observed (aIRR: 2.27, 95% confidence interval: 1.45-3.55). Among 45 patients with ALT elevation observed during the risk period, the normalization occurred in 35 patients. The 11 patients experienced a relapse of ALT elevation, while no patients receiving folic acid supplementation showed a relapse of ALT elevation.

Conclusion: Methotrexate treatment in children with inflammatory diseases increases the risk of liver enzyme elevation, highlighting the necessity of liver function monitoring. Folic acid supplementation may help mitigate the exacerbation of MTX-induced liver injury in pediatric patients.

Background: Lacosamide and perampanel are two novel antiepileptic drugs with distinct mechanisms of action. However, the real-world evidence of adverse events (AEs) related to these drugs in children is limited.

Objectives: This study aims to explore the AE profiles of lacosamide and perampanel in children by mining the FDA Adverse Event Reporting System (FAERS).

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

Methods: Reports were collected and analyzed from the first quarter of 2009 to the third quarter of 2024. Four disproportionality analysis were employed in data-mining process to detect signals in children, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the multiitem gamma Poisson shrinker algorithms.

Results: A total of 1017 AE reports of lacosamide and 349 AE reports of perampanel deemed as the "primary suspect" were retrieved in children. After being categorized and summarized by the number of reports in system organ class, the top 3 for lacosamide were nervous system disorders, general disorders and administration site conditions, injury, poisoning and procedural complications, the top 3 for perampanel were psychiatric disorders, nervous system disorders, infections, and infestations. Both lacosamide and perampanel had significant effects on the nervous system. Lacosamide was more prone to multidrug resistance and cardiac disorders, while perampanel was more likely to affect psychiatric system.

Conclusion: Our study identified potential new AE signals for lacosamide and perampanel. The findings warned the need for cautious therapeutic decisions during pregnancy and emphasized the importance of rational use of drugs and correct medication education. This postmarketing study provided reference data for the clinical monitoring and treatment of lacosamide and perampanel in children. Our study merely proved the statistical correlations; further research is needed to clarify the causal relationship between the drug and the AEs.

Background: Vancomycin exhibits high pharmacokinetic variability, particularly in hematopoietic stem cell transplantation (HSCT) patients, where augmented renal clearance (ARC) may compromise therapeutic exposure. This variability necessitates individualized dosing strategies to ensure optimal treatment efficacy.

Objective: To evaluate the pharmacokinetic variability of vancomycin in pediatric and adult patients undergoing HSCT and to assess the association of ARC with serum drug concentrations.

Design: A retrospective cohort study.

Methods: We analyzed medical records of post-HSCT patients with febrile neutropenia who received intravenous vancomycin at a tertiary hospital in Lima, Peru. Vancomycin plasma concentrations were assessed at baseline and after dose adjustments. Pharmacokinetic parameters were estimated using Bayesian modeling via PrecisePK software. Regression models were used to evaluate associations between creatinine clearance and vancomycin area under the curve (AUC).

Results: A total of 40 post-HSCT patients were included, 50% of whom were female. The median age was 17.0 years (interquartile range (IQR): 12.0-39.5), with 25% belonging to the pediatric group. The most frequent disease was B-cell acute lymphoblastic leukemia (47.5%). A significant change was observed in the vancomycin area under the curve (AUC_0-24/MIC) before and after dose adjustment (343 mg h/L vs 523 mg h/L; p < 0.001). The median relative dose adjustment percentage of vancomycin was 45% (IQR: 20-73.3). In the multivariate linear regression model, an increase in creatinine clearance was associated with a lower vancomycin AUC (β = -0.67; 95% CI: -1.14 to -0.19). This relationship was maintained after bootstrap resampling with 3000 repetitions (β = -0.67; 95% CI: -1.11 to -0.23). Sepsis was associated with the development of ARC (aRR: 1.378; 95% CI: 1.164-1.631), and as age increased, the risk of ARC decreased (aRR: 0.991; 95% CI: 0.99-0.996).

Conclusion: Most post-HSCT patients had subtherapeutic vancomycin levels at the beginning of treatment, which were optimized through individualized adjustments. The pharmacokinetic variability associated with ARC in young patients and those with sepsis supports the use of AUC-based therapeutic drug monitoring over trough concentration monitoring. These findings also highlight the importance of early renal function monitoring in patients treated with HSCT.

Background: Congenital anomalies represent a significant public health concern, with maternal drug exposure during pregnancy being a potential modifiable risk factor. While certain medications, such as antiepileptics, are well-documented for teratogenic risks, the safety profiles of many other drug classes during pregnancy remain understudied.

Objective: Leveraging the FDA Adverse Event Reporting System (FAERS), this study aimed to systematically evaluate associations between specific medications and neonatal (<28 days old) congenital anomalies potentially related to maternal drug exposure through large-scale pharmacovigilance analysis.

Design: A retrospective pharmacovigilance study was conducted by comprehensively searching the FAERS database to identify drugs potentially associated with congenital anomalies.

Methods: We reviewed all reports from the FAERS database from January 2004 to December 2022, using the criteria of age less than 28 days and outcomes of congenital anomalies. Signal detection methods, including the Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Multi-Item Gamma Poisson Shrinker, were employed to determine the associations between specific drugs and congenital anomalies, with a focus on potential teratogenic effects.

Result: We reviewed 22,263,916 cases in the FAERS database and identified the association between 91 drugs and congenital anomalies, yielding 610 positive signals. Notably, specific drugs, including olanzapine and quetiapine among antipsychotics, valproate and topiramate among antiepileptics, sertraline, paroxetine, citalopram, escitalopram, and bupropion among antidepressants, and amlodipine and sartans among antihypertensives, exhibited higher teratogenic risks compared to their counterparts. Additionally, the use of omeprazole and metronidazole may lead to an increased risk of teratogenesis.

Conclusion: Our research offers a thorough examination of teratogenic risks across different drug categories using data from the FAERS database, which can enhance the safety of medication use during pregnancy and inform clinical decision-making.

Background: Underrepresentation of various populations in clinical trials limits our understanding of efficacy and safety outcomes, as individuals with diverse backgrounds can respond differently to the same interventions. Inclusion of diverse groups in device clinical trials is essential for providing innovative, patient-centric solutions and achieving health equity.

Objective: To evaluate how social determinants correlate with safety events in clinical trials with medical devices to identify safety signals, improve safety profiles, and develop risk-based safety and quality management strategies.

Design: A single-center, retrospective study was conducted for clinical trials with medical devices at a safety-net hospital.

Methods: Data obtained from 223 patients randomized into 19 device clinical trials were assessed retrospectively for correlation of social determinants of health variables and study protocol complexity with study protocol deviations, adverse events, and study dropout rates by using the Kruskal-Wallis and Spearman correlation tests.

Results: Lower median income was associated with an increased number of adverse events (r = -0.18599, p = 0.0053) and protocol deviations (r = -0.27349, p < 0.0001). Higher study protocol complexity was associated with an increased number of adverse events (r = 0.55328, p < 0.0001) and a higher number of protocol deviations (r = 0.54079, p < 0.0001). Out of 701 adverse events reported, 472 were serious adverse events, and 3.8% of serious adverse events were related to the study device. Multiple comorbidities >3 were associated with an increased number of safety events and protocol deviations (r = 0.35929, p < 0.001; r = 0.17270, p = 0.0098, respectively).

Conclusion: Examining the root causes of these outcomes, as well as patient-centric medical management, can improve data integrity and aid risk-based safety and quality management in device clinical trials.

Background: Pharmacovigilance is essential for ensuring patient safety, and hospital pharmacists play a key role in this system. However, their knowledge, attitudes, and practices (KAP) remain understudied in China.

Objectives: To evaluate the KAP of hospital pharmacists toward pharmacovigilance in China.

Design: Nationwide, cross-sectional study.

Methods: This study evaluated the KAP of 9724 hospital pharmacists from 2145 hospitals across all 31 provinces of mainland China using a structured questionnaire and a multi-stage sampling approach. Descriptive statistics were used to summarize the KAP of the participants, and multivariable logistic regression was applied to explore the influencing factors of high KAP performance.

Results: The proportions of respondents achieving high performance (score ⩾4 out of a maximum of 5) in knowledge, attitudes, and practices were 22.2%, 44.2%, and 68.0%, respectively, with significant correlations between these dimensions (p < 0.001). Misconceptions were prevalent, with 50.1% of pharmacists incorrectly attributing pharmacovigilance responsibility to medical institutions instead of marketing authorization holders (MAHs), and 36.2% misunderstanding pharmacovigilance as solely adverse drug reaction (ADR) reporting. A total of 95.5% of respondents expressed a willingness to participate in pharmacovigilance training. The reporting of ADEs/ADRs, medication errors, and drug quality problems to regulatory authorities is well-established nationwide, but 27.8% infrequently or never reported serious ADRs to pharmaceutical companies. Higher educational levels, hospital tiers, and leadership roles positively influenced knowledge and attitude, while male pharmacists showed superior practices compared to females. Clinical pharmacists and team leaders outperformed dispensing pharmacists in all KAP dimensions.

Conclusion: Our study reveals a significant scope for enhancement in the KAP of hospital pharmacists pertaining to pharmacovigilance in China. Specifically, there is a critical need to improve the understanding of pharmacovigilance's scope and responsibilities, and fostering stronger collaborative efforts between medical institutions and MAH is imperative, particularly within targeted pharmacist groups.