Therapeutic Advances in Drug Safety最新文献

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.

Background: Methotrexate is central to the management of rheumatoid arthritis (RA). However, its use is often limited by methotrexate intolerance.

Objectives: This study aims to explore the association between alternative methotrexate dosing methods and methotrexate intolerance.

Design: A cross-sectional study.

Methods: A cross-sectional survey was conducted on patients with RA receiving methotrexate for at least 3 months at the outpatient clinic of King Saud University Medical City, Riyadh, Saudi Arabia. The electronic survey collected data on demographics, marital and educational status, methotrexate use, Methotrexate Intolerance Severity Score (MISS), and Health Assessment Questionnaire. Statistical analyses (univariate and linear or logistic regression) were conducted to evaluate the associations between the administration methods and methotrexate intolerance (MISS ⩾6).

Results: The study included 154 patients, predominantly female (89%; mean age (standard deviation, ±SD): 50 (±12) years). Methotrexate tolerance was observed in 64% of the participants, while 36% had a MISS above the cutoff point of 6, indicating intolerance. Methotrexate-intolerant patients were younger (mean age (±SD): 47 (±12) years) than tolerant patients (mean age (±SD): 54 (±12) years; p = 0.005). No significant differences were found between methotrexate-tolerant and methotrexate-intolerant patients regarding dose, frequency, relation to meals, and time of day.

Conclusion: Methotrexate tolerance was not associated with different administration methods: split-dose versus single weekly dose, or subcutaneous versus oral administration.

Background: The analysis and interpretation of pharmacovigilance data is an essential component of the continuous benefit-risk assessment of authorised medicinal products. Effective pharmacovigilance data analysis starts with data collection and involves critical activities, such as signal detection, that enable the generation of new information on marketed products, and inform safety-related regulatory actions. This real-time pharmacovigilance data analysis, which requires efficient collaboration and exchange of information between the key pharmacovigilance stakeholders, represents a challenge for many low- and middle-income countries (LMIC).Objectives:: To assess the capacity for analysis of pharmacovigilance data in LMIC and to identify mechanisms to strengthen data analysis, interpretation and evidence-based pharmacovigilance decision-making.

Design: We used a convergent parallel mixed-methods study design consisting of qualitative and quantitative methods.

Methods: Qualitative and quantitative methods consisted of semi-structured interviews and an online survey, respectively. Quantitative research was complemented by cross-sectional analyses of the number of adverse event reports from LMIC in VigiBase^® from 2019 to 2023.

Results: Nine key informants from eight countries were interviewed and 50 respondents from 34 countries completed the online survey. Four major themes emerged from the data and are proposed as transformative actions to strengthen pharmacovigilance data analysis and interpretation in LMIC: build on existing pharmacovigilance data analysis capacity rather than create new or parallel mechanisms; implement standardised procedures to enable efficient data analysis; augment the work of the safety committees by assigning pharmacovigilance staff to data analysis; and implement mechanisms that allow benefit-risk evaluation and decision-making.

Conclusions: Findings from this research revealed that many LMIC have implemented procedures for reporting and collecting suspected adverse events, but a considerable proportion of the data collected is not analysed in-country due to a lack of requisite knowledge, processes and structures to support such analysis. Establishing the four essential elements proposed by this research will equip LMIC for efficient data analysis, thereby supporting consistent decision-making through pharmacovigilance.

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.