Therapeutic Advances in Drug Safety最新文献

Background: Antibody-drug conjugates (ADCs), as a new type of targeted drug, have been widely used in breast cancer patients in recent years. However, while achieving better efficacy, its hepatotoxicity should not be ignored.

Objectives: To clarify the incidence of hepatotoxicity associated with ADCs and compare the incidence of hepatotoxicity of ADCs with different drugs.

Design: We performed a systematic review and meta-analysis to summarize the clinical trials and combined the data using meta-analysis.

Methods: We searched the PubMed, Embase, and Web of Science databases up to March 12, 2023. The primary outcome was the incidence of ADC-related hepatotoxicity in breast cancer patients. The data were merged using Stata 17.0 software.

Results: ADCs caused a high incidence of all grades of hepatotoxicity. Sacituzumab govitecan caused the highest incidence of all grades of alanine aminotransferase (ALT) elevation at 25.30% (95% confidence interval (CI): 19.29-31.82). Trastuzumab deruxtecan caused the highest incidence of all grades of aspartate aminotransferase (AST) elevation. The highest incidence of AST elevation was 31.89% (95% CI: 18.56-46.85). Conversely, trastuzumab emtansine caused the highest incidence of grade ⩾3 AST and ALT elevation (incidence rates were 3.95% (95% CI: 2.39-5.85) and 3.42% (95% CI: 1.95-5.24), respectively).

Conclusion: Hepatotoxicity is an adverse reaction that cannot be ignored when ADCs are used for treating breast cancer. Moreover, clinicians should pay more attention to the assessment of patients' liver function and monitoring of liver indices, particularly ALT and AST, when using ADCs.

Background: Aripiprazole and risperidone, widely used atypical antipsychotics, are commonly adjunctively prescribed in clinical practice. When aripiprazole was combined with risperidone, the genotype of drug-metabolizing enzymes and liver impairment may lead to complex pharmacokinetic changes. The Physiologically Based Pharmacokinetic (PBPK) model can predict the influence of these factors on plasma concentration and optimize dosage regimens.

Objectives: This study aims to investigate the pharmacokinetic changes of aripiprazole caused by various influencing factors when it was co-administered with risperidone through PBPK models.

Design: The PBPK models of aripiprazole and risperidone were developed by gathering physicochemical parameters and drug-specific parameters. Then, by combining the inhibitory parameters, the enzymatic kinetic parameters of CYP2D6 genotypes, and the changes in anatomical and physiological parameters when liver function is damaged, the corresponding PBPK models were further established. Finally, this study put forward dosage optimization recommendations for situations where risks may exist.

Methods: The comparison between predicted and observed plasma concentration data, along with the assessment of pharmacokinetic parameters, was utilized to evaluate the fit performance of the models.

Results: The simulations of the PBPK model revealed that co-administration of risperidone did not result in significant changes in aripiprazole pharmacokinetics. However, in individuals with mild hepatic impairment and CYP2D6 normal metabolizer, a dose reduction of approximately 11% was advised when aripiprazole was combined with risperidone. When individuals with mild liver damage have CYP2D6 genotypes of intermediate metabolizer (IM) and poor metabolizer (PM), aripiprazole doses should be further reduced to 61% and 51%, respectively.

Conclusion: The co-administration of aripiprazole and risperidone is generally considered safe from a pharmacokinetic perspective. However, if individuals have a CYP2D6 genotype of IM or PM and/or if they have mild hepatic impairment, adjusting the dose of aripiprazole is advisable to mitigate potential risks when combining it with risperidone.

Introduction: Clozapine, an antipsychotic used in the treatment of schizophrenia, is known for its serious side effects. In order to promote patient safety, drug-drug interaction (DDI) databases can be consulted by clinicians. In this study, the degree of consensus between five sources on DDIs with clozapine is determined.

Methods: The summary of product characteristics of clozapine, Delphicare interaction database, Stockley's interaction checker, the Lexicomp interaction database, and the interaction database of Clinical Pharmacology are included. By comparing the original categories assigned to interactions with clozapine by the included DDI sources, a degree of consensus between sources is determined. Furthermore, based on the combined information, an evaluation on the severity of each potential interaction is made.

Results: One hundred eighty-three potential DDIs with clozapine are retrieved from the five included sources. A consensus between sources is found in 47.5% (n = 87) of DDIs.

Conclusion: This study shows major discrepancies between five different sources on DDIs with clozapine. The potential impact of the use of one specific database on patient safety and prescribing behavior could prove to be problematic.

Background: Inappropriate medication prescribing in older patients increases the risk of poorer health outcomes and increased costs. The IMMENSE trial, integrated a clinical pharmacist into the health care team, to improve medication therapy among older patients, and to investigate the impact on acute revisits to hospital.

Objectives: This study investigated the prevalence of potentially inappropriate medications (PIMs) and prescribing omissions (PPOs) at hospital admission and discharge. It also explored the impact of the pharmacist intervention on PIMs and PPOs, and other factors associated with PIMs and PPOs at discharge.

Design: The STOPP/START criteria version 2 were retrospectively applied at admission and discharge. PIM and PPO changes were compared, and Poisson regression was used to assess factors influencing prevalence at discharge.

Results: At hospital admission, PIM prevalence was 58.6% among intervention patients and 64.8% among control patients. PPO prevalence was 55.3% and 55.5%, respectively. A larger proportion of PIMs identified at admission were resolved by discharge in the intervention group (42.9%) compared to the control group (27.4%). No difference was seen for PPOs. Poisson regression identified a significantly higher risk for PIMs at discharge in the control group compared to the intervention group (IRR 1.255; 95% CI 1.063-1.480, p = 0.007), but no effect for PPOs. Patients living in a nursing home, a home care facility, or an institution showed a higher risk of PPOs at discharge compared to patients living at home (IRR 1.378; 95% CI 1.156-1.644, p < 0.001).

Conclusion: The IMMENSE intervention significantly reduced the risk of PIMs at discharge, with no effect on PPOs. Living in nursing homes, home care facilities, or institutions prior to hospitalization increased the risk of PPOs at discharge. Pharmacists may contribute to improved medication appropriateness in older hospitalized patients.

Background: Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other medicine/vaccine-related problem. Since its inception in the 1960s, PV has undergone continuous evolution, progressing from a basic level mainly focused on the collection and analysis of cases in its earliest years to a complex system regulated by rigorous standards and laws with modern PV. In recent years, PV has faced the challenge of adapting to rapid scientific advancements, the complexity of the pharma industry, and the digital revolution. To better understand the current state and future developments of PV within pharma companies, the PV working group "Ernesto Montagna" of the Italian Society of Pharmaceutical Medicine (SIMeF ETS) conducted a national survey in Italy.

Objectives: The main objective of this survey was to explore the current state and future developments of PV within Pharmaceutical Companies in Italy.

Design: This study was designed as a national survey targeting members of the Italian Society of Pharmaceutical Medicine (SIMeF ETS).

Methods: The survey utilized computer-assisted web interview (CAWI) technology to collect data from SIMeF members across affiliate and corporate companies, aiming to explore expectations for PV. A simplified version of the questionnaire was also sent to members of the Clinical Research and Medical Affairs (RICMA) and Real-World Evidence working groups of SIMeF to gather input from RICMA professionals regarding the role of PV in pharma companies.

Results: The survey revealed that PV in pharma companies is undergoing a transformation, with the potential for greater strategic alignment with business objectives and stakeholder focus. However, there is still room for improvement, particularly in terms of perception within other company departments. It is evident that PV's evolution has only just begun.

Conclusion: A critical factor in the evolution of PV is the adoption of a holistic and comprehensive approach to activities and processes. Scientific associations such as SIMeF can play a valuable role in cultivating new skills and capabilities among PV professionals, assisting, and supporting this change.

Background: Outpatient hysteroscopic surgery requires patients to be anaesthetised and recover quickly, and the drugs used must be safe and effective. Remifentanil is typically co-administered with propofol as total intravenous anaesthesia (TIVA) for hysteroscopy because of its favourable pharmacokinetic and pharmacodynamic properties. However, the optimal dose of remifentanil when co-administered with propofol without neuromuscular blocking agents (NMBAs) has not been established.

Objectives: In this sequential dose-finding study, the 90% effective dose (ED90) of remifentanil effect-site concentration (Ce) combined with propofol without NMBAs during outpatient hysteroscopy was calculated to minimise the side effects of using higher doses.

Design: This sequential dose-finding study was conducted in August 2022.

Methods: Forty patients who underwent outpatient hysteroscopy under TIVA were included in the study. With a biased coin up-and-down design, the initial remifentanil Ce was established at 2 ng/mL, and the subsequent remifentanil dosage was determined based on the reaction of the previous patient. The primary outcome was a remifentanil Ce that resulted in successful TIVA by maintaining a Narcotrend index < 60, surgical pleth index (SPI) < 50, and without patient movement throughout hysteroscopy. Secondary outcomes included rates of hypotension-related symptoms and interventions, drug consumption, post-anaesthesia care unit (PACU)-estimated visual analogue scale (VAS) and Ramsay sedation scores, modified Aldrete scores, and other adverse effects of anaesthesia. The ED90 and 95% confidence intervals (CI) were estimated using isotonic regression methods and bootstrapping.

Results: For TIVA without NMBAs during outpatient hysteroscopy, the ED90 Ce of remifentanil combined with propofol was determined to be 2.75 ng/mL (95% CI, 2.50-3.00 ng/mL). The incidence of peri-operative adverse effects of anaesthesia was relatively low. All the patients had satisfactory VAS, Ramsay sedation, and modified Aldrete scores in the PACU.

Conclusion: Remifentanil at a Ce of 2.75 ng/mL is recommended for TIVA combined with propofol in outpatient hysteroscopic surgery.

Trial registration: http://www.chictr.org.cn (ChiCTR2200062284; 31/7/2022).

Background: The administration of either alfentanil or sufentanil as a single injection, combined with target-controlled infusion (TCI) of propofol, represents a frequently employed anesthetic regimen for daytime hysteroscopy.

Objectives: This study was designed to evaluate and compare the safety and efficacy of alfentanil and sufentanil in the context of daytime hysteroscopy.

Design: A total of 160 patients, scheduled for daytime hysteroscopy, were randomly allocated into two groups: Group A and Group S respectively received alfentanil 10 μg/kg or sufentanil 0.15 μg/kg as a single intravenous injection. Both groups were given propofol with TCI for sedation.

Methods: Monitoring of vital signs was conducted from pre-anesthesia through to 2 h postoperatively. The primary outcome measured was hypoxemia, defined as SpO₂ levels below 92% for a duration of 30 s, which necessitated manual positive pressure ventilation. Secondary outcomes included various perioperative complications, such as postoperative nausea and vomiting (PONV) occurring 2 h after surgery, as well as hemodynamic indicators, NRS scores for pain, and other anesthesia-related data. This comprehensive dataset was meticulously documented and subsequently analyzed for comparative purposes.

Results: The analyses revealed that Group A had a significantly lower incidence of hypoxemia (p = 0.002) and PONV (p = 0.021). Additionally, group A demonstrated overall more stable blood pressure and heart rate, as well as higher SpO₂ levels.

Conclusion: For daytime hysteroscopy, alfentanil at a dose of 10 μg/kg is safer than sufentanil at a dose of 0.15 μg/kg when combined with propofol TCI.

Trial registration: This study was registered with the Chinese Clinical Trial Registry (The URL of registration is https://www.chictr.org.cn/showproj.html?proj=177784; registration number: ChiCTR2200063939). The date of first registration was September 21, 2022.

Background: Self-treatment of dietary supplements may contribute to interactions and severe side effects. Limited studies have constructed a scale that can measure the disclosure practice of supplements to healthcare providers and the influencing factors.

Objective: The study aims to investigate the supplement disclosure practice among the public in the UAE using a developed and validated supplement disclosure assessment scale tool.

Design: A cross-sectional survey study that targeted those residing in the United Arab Emirates (UAE) aged 18 years and above from both genders through an online survey.

Methods: A novel scale tool was developed and examined for its validity and reliability through three pilot studies.

Results: The study included three validity and reliability pilot studies before the main study evaluation: pilot 1 (n = 104), pilot 2 (n = 101), pilot 3 (n = 37), and study data (n = 407). A total of 407 respondents provided feedback from which 137 stated that they consumed supplements. A significant indirect effect of healthcare provider initiation of enquiry (HPE) on patient-informing practice (PI) was observed through two mediating variables, patient's beliefs (PB) and pharmacist counseling regarding supplements interactions (PC) (B = 0.106, t = 2.120, p = 0.03 and B = 0.077, t = 2.011, p = 0.04, respectively). Most respondents were not asked about their supplement consumption by the hospital and community pharmacists (52.94 and 50.74, respectively). Most respondents (54.89%) stated that pharmacists did not counsel them about any possible interaction of supplements with laboratory tests. The mean construct scores were 1.096 for PI, 2.618 for PC, 1.552 for HPE, and 1.412 for PB.

Conclusion: The instrument demonstrates desirable validity and reliability. The study results revealed a direct effect of PB and PC on the supplement disclosure practice. HPE indirectly affected PI through two mediating variables: PB and PC. The results showed a moderate HPE and PC and an excellent PB and PI construct.

Background: Deprescription of medications for older people in long-term care settings is crucial to enhance medication safety by reducing polypharmacy and minimizing related adverse events. Nurses as the member of the multidisciplinary healthcare team can support deprescription initiatives, but there is a gap in comprehensive knowledge about their roles.

Objectives: To investigate the role and contribution of nurses in deprescribing medications within the multidisciplinary pharmaceutical care context of long-term healthcare for older people.

Design: A systematic review utilizing an integrative approach was performed.

Methods: Multiple databases were searched, including PubMed (covering MEDLINE), Scopus, CINAHL, ProQuest and Embase, focusing on studies published in English from 2014 to 2024. The preliminary search yielded 4872 studies, which were then refined to 32 qualitative and quantitative studies chosen for data analysis and narrative synthesis. Thematic comparisons and analysis led to the creation of meaningful categories integrating the studies' findings to meet the review's objective.

Results: The review findings were classified into categories: 'necessity and benefits of deprescribing', 'multidisciplinary collaboration for deprescribing', 'nurse role in deprescribing', 'identified challenges to deprescribing', 'involvement of older people and families in deprescribing'. They illustrated and exemplified various aspects of nurses' roles and contributions in deprescription initiatives within the multidisciplinary pharmaceutical care team, such as support for reducing doses, discontinuing medications or transitioning to safer alternatives, as well as factors influencing this process.

Conclusion: The main dimensions of nurses' roles and contributions in deprescription initiatives encompass monitoring, communicating and educating. Challenges to nurses' active participation in deprescribing, such as the need for increased knowledge, confidence and inclusion in team discussions, should be addressed through education, training and changing attitudes. These steps are essential for improving the safety of medication deprescribing in long-term care settings.

Trial registration: The review was registered under PROSPERO ID: CRD42023486484, and can be accessed at crd.york.ac.uk/PROSPERO/display_record.php?RecordID=486484.