Therapeutic Advances in Drug Safety最新文献

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.

Background: Valproate (valproic acid, sodium valproate) is authorised in Montenegro for epilepsy and bipolar disorder treatment. Due to known teratogenicity, risk minimisation measures were introduced in 2014 and further reinforced in 2018 by the implementation of the Pregnancy Prevention Programme (PPP). Despite these measures, consumption of valproate in Montenegro increased in the period 2016-2022.

Objectives: To investigate the effects of risk minimisation measures on valproate prescription in Montenegro.

Design: A retrospective, observational, 7-year, nationwide study.

Methods: The Primary Health Care Information System (PHCIS) was used as a data source. The health records of women of childbearing potential (12-55 years) for the period 2016-2022 were analysed. Additionally, unstructured data were reviewed to determine the number and characteristics of valproate-exposed pregnancies. The software PASW, version 25.0 (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis.

Results: A total of 2247 women of childbearing potential using valproate were identified during the observed period. The number of patients using valproate for epilepsy treatment decreased by 24% while the use of valproate in psychiatry increased by 45% over the observed period. The age of the patient was the only predictive factor for successful PPP implementation (chi-square = 35.811, df = 4 and p < 0.001). The odds ratio (OR) for the age category was 1.22 (95% CI: 1.10-1.35). Contraception prescription was recorded in only 1.5% of patients following the PPP implementation. A total of 11 cases of exposed pregnancies were identified, while epilepsy was the indication in 5 (45%) cases.

Conclusion: Regulatory risk minimisation measures had a limited impact on reducing the risk of valproate teratogenicity in Montenegro, with the most success in the group of youngest patients. Measures were more effective in the epilepsy indication. The rising use of valproate for psychiatric indications is concerning. Targeted education, better preconception care and improved coordination among healthcare professionals are necessary.

Background: Prescribing psychotropic drugs often leads to long-term use in people with intellectual disabilities. In this population, polypharmacy is also common, likely because of the high frequencies of comorbid somatic, behavioural and mental disorders, while the vulnerability for medication side effects is high. Therefore, there is a risk of inappropriate prescribing of psychotropic drugs in people with intellectual disabilities.

Objectives: This study aimed to develop a tool to assess the appropriateness of psychotropic drug prescriptions in people with intellectual disabilities and to test its psychometric properties.

Design: In this study, we used a mixed-methods design. In a qualitative phase, we developed the tool, followed by a quantitative phase, to evaluate its psychometric properties.

Methods: We used a modified Delphi procedure consisting of a preparation phase and three Delphi iterations to develop the tool and to determine which items encompass the concept of appropriate psychotropic drug prescribing. A weighting round was conducted to determine a summated index score. Finally, the test-retest reliability, the interrater reliability and the convergent validity of the tool were investigated.

Results: The Delphi panel, with 37 field expert participants, agreed on the content of the tool, including seven domains (indication, dosage, duration, duplication, interactions, evaluation of effect and evaluation of side effects) that should be assessed regarding appropriate psychotropic drug prescribing. The test-retest reliability and the interrater reliability turned out to be moderate to perfect for five of the seven domains, except the domains 'evaluation of effect' and 'evaluation of side effects', although no interrater agreement was found in the domain 'duration'. The convergent validity was slight.

Conclusion: In conclusion, this study resulted in the development of a reliable tool to support prescribers in clinical practice in the appropriate prescribing of psychotropic drugs in people with intellectual disabilities.

Background: There are still some points of controversy regarding the adverse events associated with celecoxib use, particularly in terms of thrombosis.

Objectives: To explore the relationship between celecoxib and thrombosis in the real world and to investigate the causality that exists.

Design: We conducted pharmacovigilance analysis on spontaneously reported adverse events to evaluate the association between celecoxib and thrombotic events. In addition, Mendelian randomization studies of drug targets were used to explore the causal relationship between them.

Methods: This study used the data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Report database, and the Canada Vigilance Adverse Reaction (CVAR) for pharmacovigilance analysis. Among these, the Report Odds Ratio, Proportional Reporting Ratio, Information Component, and Empirical Bayesian Geometric Mean were used to determine the strength of adverse event signals. In addition, the Weibull shape parameter test was used in this study to investigate the trend of adverse events. Mendelian randomization was used to explore the causal link between celecoxib and deep vein thrombosis.

Results: Pharmacovigilance signals indicated that celecoxib was associated with an increased risk of thrombosis, with deep vein thrombosis demonstrating positive signals in all three populations. In addition, Mendelian randomization analyses provided evidence to support a causal relationship between celecoxib and deep vein thrombosis and clarified that carbonic anhydrase 2, a target protein of celecoxib, is causally linked to deep vein thrombosis.

Conclusion: The use of celecoxib leads to an increased risk of thrombosis and suggests a causal relationship.

Background: Intranasal (IN) esketamine has become an effective and well-tolerated therapeutic option for the management of treatment-resistant depression within major depressive disorder (MDD-TRD). Despite these promising benefits, given the prevalence of ketamine abuse, concerns remain over the addiction liability that may be associated with esketamine treatment.

Objectives: The objective of this study is to assess the real-world abuse liability of this substance by tracking changes in likeability and cravings through an acute treatment course.

Design: This is a secondary analysis of a previously published multicenter observational study.

Methods: Likeability and craving for esketamine were assessed using the Likeability and Cravings Questionnaire (LCQ) in MDD-TRD patients receiving an acute course of IN esketamine treatment (eight dosing sessions). The data were analyzed using descriptive statistics, multivariate analysis of variance (MANOVA), and pre-post effect size (Cohen's d).

Results: Twenty-three patients (52.2% female, 43.5 ± 11.9 years old) were assessed. Most patients reported a neutral liking and no cravings for esketamine after their first dosing session. These metrics did not increase significantly by treatment endpoint. MANOVA showed that neither age, sex, baseline depression scores, the presence of side effects, or the study site had a statistically significant impact on LCQ scores either alone or in combination.

Conclusion: These results agree with the available literature, showing that an acute course of IN esketamine treatment was not associated with high levels of drug liking or cravings, and this did not increase through the course of eight treatments. Though larger studies are needed, esketamine does not appear to be associated with significant abuse liability when used in an acute course of treatment for patients with MDD-TRD. These are important results for this patient population and for clinical practice.