European Journal of Clinical Pharmacology最新文献

{"title":"Genome-wide association study of direct oral anticoagulants and their relation to bleeding.","authors":"Sofia Attelind, Niclas Eriksson, Mia Wadelius, Pär Hallberg","doi":"10.1007/s00228-025-03821-x","DOIUrl":"https://doi.org/10.1007/s00228-025-03821-x","url":null,"abstract":"<p><strong>Purpose: </strong>Direct oral anticoagulants (DOACs) are used to prevent and treat thromboembolic events in adults. We aimed to investigate whether pharmacogenomic variation contributes to the risk of bleeding during DOAC treatment.</p><p><strong>Methods: </strong>Cases were recruited from reports of bleeding sent to the Swedish Medical Products Agency (n = 129, 60% men, 93% Swedish, 89% on factor Xa inhibitors) and compared with population controls (n = 4891) and a subset matched for exposure to DOACs (n = 353). We performed a genome-wide association study, with analyses of candidate single nucleotide polymorphisms (SNPs) and candidate gene set analyses.</p><p><strong>Results: </strong>Forty-four cases had major, 37 minor, and 48 clinically relevant non-major (CRNM) bleeding. When cases were compared with matched controls, BAIAP2L2 rs142001534 was significantly associated with any bleeding and major/CRNM bleeding (P = 4.66 × 10^-8 and P = 3.28 × 10^-8, respectively). The candidate SNP CYP3A5 rs776746 was significantly associated with major and major/CRNM bleeding (P = 0.00020 and P = 0.00025, respectively), and ABCG2 rs2231142 was nominally associated with any bleeding (P = 0.01499). Rare coding variants in the candidate gene VWF were significantly associated with any bleeding (P = 0.00296).</p><p><strong>Conclusion: </strong>BAIAP2L2, CYP3A5, ABCG2, and VWF may be associated with bleeding in DOAC-treated patients. The risk estimates of the candidate variants in CYP3A5 and ABCG2 were in the same direction as in previous studies. The Von Willebrand Factor gene (VWF) is linked to hereditary bleeding disorders, while there is no previous evidence of bleeding associated with BAIAP2L2.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143673428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of cigarette smoking on drugs' metabolism and effects: a systematic review.","authors":"Stefano Zanni, Jole Del Prete, Alessandra Capogrossi, Giuseppe Papapietro, Angela Del Cimmuto, Sergio Gazzanelli, Andrea Caronna, Carmela Protano","doi":"10.1007/s00228-025-03817-7","DOIUrl":"https://doi.org/10.1007/s00228-025-03817-7","url":null,"abstract":"<p><strong>Purpose: </strong>Cigarette smoke continues to be widely used around the world and it contains several substances that can affect the pharmacokinetics and/or pharmacodynamics of medications, altering their safety and effectiveness. The aim of this systematic review was to summarize the scientific evidence regarding possible changes in the pharmacokinetics and/or pharmacodynamics of drugs induced by cigarette smoking, possible mechanisms of action and related effects.</p><p><strong>Methods: </strong>The systematic review was performed according to the PRISMA Statement and the protocol was registered on the PROSPERO platform (CRD42023477784). Pubmed, Scopus, Web of Science databases were used. We considered observational, semi-experimental or experimental studies written in English and published between January 1, 2000, and November 13, 2024, focused on smoking subjects (healthy volunteers or patients) receiving any kind of medication. Data regarding possible modifications in drugs' pharmacokinetics and/or pharmacodynamics induced by cigarette smoking were assessed. The quality of observational studies and experimental studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale and the Jadad Scale, respectively.</p><p><strong>Results: </strong>In total, 37 studies were included, and 31 of them showed relevant modifications in the pharmacokinetics or effects of the drugs in smokers compared to non-smokers. Most of the included studies (n = 20) investigated drugs for psychiatric or neurological disorders, showing a reduction in plasma concentration or an increase in drug clearance in smokers as well as antibiotics metronidazole and cycloserine. Besides, seven articles focused on anticancer drugs indicating an increase in drug metabolism. The remaining articles reported effects of smoking on the metabolism of other drugs, such as cardiovascular drugs, phosphodiesterase 5 inhibitors, local anesthetics and medications for musculoskeletal or chronic obstructive pulmonary diseases. Induction of the cytochrome enzyme CYP1A2 is the most common mechanism mediating the reduction of drug concentrations by cigarette smoking.</p><p><strong>Conclusion: </strong>The results indicate an increased risk of therapeutic failure for smokers and represent further motivation to encourage smoking cessation or attention in formulating personalized therapy.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143669481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unveiling cardiovascular and respiratory toxicities with monoclonal antibodies in multiple myeloma: disproportionality analysis from the FDA Adverse Event Reporting System.","authors":"Maria Antonietta Barbieri, Giulia Russo, Giuseppe Cicala, Giuseppe Andò, Tindara Franchina, Nicola Silvestris, Mariacarmela Santarpia, Edoardo Spina","doi":"10.1007/s00228-025-03824-8","DOIUrl":"https://doi.org/10.1007/s00228-025-03824-8","url":null,"abstract":"<p><strong>Introduction: </strong>Monoclonal antibodies (mAbs) have revolutionized the treatment of multiple myeloma (MM), demonstrating remarkable effectiveness, despite potential adverse events (AEs). This study aims to identify unexpected signals of disproportionate reporting (SDRs) for cardiovascular (CV) and respiratory AEs associated with mAbs in MM treatment.</p><p><strong>Methods: </strong>From January 2015 to December 2023, reports involving suspected drugs (daratumumab, elotuzumab, elranatamab, isatuximab, belantamab mafodotin, teclistamab, and talquetamab) were analyzed in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Descriptive analysis was followed by disproportionality analyses first comparing mAbs to all other drugs (reference group, RG1), and subsequently conducting a sensitivity analysis against other MM drugs (RG2).</p><p><strong>Results: </strong>Out of 13,496,241 reports, 31,052 (0.2%) were associated with MM, with 6574 (0.1%) linked to CV and respiratory adverse events, primarily involving older population (n = 3441; 52.3%) and male (n = 3338; 50.8%) patients. Disproportionality analyses identified unexpected SDRs for daratumumab, including cardiac failure (n = 322; RG1: ROR = 4.74, CI 95% = 4.24-5.29; RG2: ROR = 4.42, 95% CI = 3.91-4.99), embolic and thrombotic event, such as pulmonary embolism (162; RG1: 2.44, 2.09-2.85), deep vein thrombosis (126; RG1: 2.95, 2.47-3.52), and respiratory failure (192; RG1: 4.06, 3.52-4.68; RG2: 4.2, 3.59-4.91). Isatuximab was linked to cardiac arrhythmia, such as atrial fibrillation (46; RG1: 2.54, 1.9-3.4; RG2: 1.35, 1.01-1.81), embolic and thrombotic event, including deep vein thrombosis (26; RG1: 2.93, 1.99-4.3) and pulmonary embolism (89; RG1: 6.56, 5.32-8.1; RG2: 2.93, 2.37-3.63). Elotuzumab showed also SDRs for atrial fibrillation (56; RG1: 3.68, 2.82-4.79; RG2: 1.96, 1.5-2.56) and deep vein thrombosis (41; RG1: 5.49, 4.03-7.47).</p><p><strong>Conclusion: </strong>Unexpected CV and respiratory AEs with clinical relevance not previously reported in literature have been identified underlining the importance of pharmacovigilance.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facilitators and barriers to generic and biosimilar medications in the Middle East and North Africa: insights from physicians and pharmacists-a systematic review.","authors":"Kefah Ali Alqawasmeh, Thomas Mason, Abigail Morris, Wael Hafez, Thekra Hasan, Sondos Taher, Rania Al Dweik","doi":"10.1007/s00228-025-03819-5","DOIUrl":"https://doi.org/10.1007/s00228-025-03819-5","url":null,"abstract":"<p><strong>Background: </strong>The adoption of generic and biosimilar medications is crucial for improving healthcare accessibility and cost savings in the Middle East and North Africa (MENA) region. Understanding the factors that influence their acceptance is crucial for developing effective strategies for promoting their use.</p><p><strong>Purpose: </strong>This systematic review aimed to examine the facilitators and barriers identified by healthcare professionals while prescribing and dispensing generic and biosimilar medications in the MENA region, focusing on their perceptions, knowledge, and attitudes.</p><p><strong>Methods: </strong>Following Cochrane guidelines and the \"Guidance on the Conduct of Narrative Synthesis in Systematic Reviews,\" a comprehensive search of electronic databases and grey literature was conducted from 2012 to 2024. Studies assessing physicians' and pharmacists' perspectives on generics and biosimilars in the MENA region were included. Quality appraisal was performed using a standardized tool, the mixed methods appraisal tool (MMAT). The findings were synthesized using a descriptive analysis.</p><p><strong>Results: </strong>Of the 3570 screened citations, 39 met the inclusion criteria. Among them, 25 studies addressed facilitators and barriers to adopting generic medications, whereas 15 focused on biosimilars. Facilitators of generic medications included understanding the use of generics as cost-effective substitutes, supportive government policies, generic medication awareness, and pharmacists' empowerment to substitute medications. Barriers included knowledge gaps leading to distrust in efficacy and safety, the influence of pharmaceutical companies, cultural biases favoring brand name drugs, regulatory challenges, low consumer awareness, and concerns about pharmacists' profitability. Facilitators for biosimilars were mostly similar to generics, with an added emphasis on access benefit recognition when using biosimilars. Unique barriers included concerns about the lack of long-term safety data, hesitancy toward non-medical switching, and nocebo effect concerns. The quality assessment indicated that most studies were of moderate quality, with limitations such as sample size and representativeness, validity of the measurement tools, and potential biases of the researchers.</p><p><strong>Conclusion: </strong>Significant knowledge gaps regarding regulatory approval, safety, and efficacy hinder the adoption of generic drugs and biosimilars in MENA. Targeted educational initiatives at the regulatory and payer levels are essential for bridging these gaps, enhancing awareness, and fostering acceptance. Implementing comprehensive educational programs for physicians and pharmacists is crucial to support the transition toward the greater use of generics and biosimilars.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prescribing patterns of glucagon-like peptide-1 receptor agonists in the Swedish capital region-a register-based cross-sectional study.","authors":"Alice Fors, Tomas Forslund, Anders Sundström, Björn Wettermark","doi":"10.1007/s00228-025-03823-9","DOIUrl":"https://doi.org/10.1007/s00228-025-03823-9","url":null,"abstract":"<p><strong>Purpose: </strong>Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have gained considerable media attention, but there is limited knowledge about those receiving the drugs. This study aimed to assess demographic characteristics and previous diagnoses in patients dispensed GLP-1 RAs in Region Stockholm, Sweden, between 2019 and 2023, with a focus on off-label prescribing.</p><p><strong>Methods: </strong>This was a register-based cross-sectional study including all inhabitants in Region Stockholm, Sweden, who were dispensed a GLP-1 RA between 2019 and 2023. Patient characteristics were assessed through record linkage with administrative healthcare data on demographics, healthcare consultations, diagnoses, and other dispensed drugs.</p><p><strong>Results: </strong>The prevalence proportion of GLP-1 RA dispensations in Region Stockholm increased from 4.7 patients/1000 inhabitants in 2019 to 17.5 patients/1000 inhabitants in 2023, and the incidence proportion from 1.8 patients/1000 inhabitants in 2019 to 7.4 patients/1000 inhabitants in 2023. GLP-1 RAs have become more common among a younger and female population, with women constituting 47% of incident patients in 2019 compared to 53% in 2023. The most common diagnosis shifted from type 2 diabetes mellitus (T2DM) (82% in 2019) to obesity (47% in 2023). During the same period, obesity without T2DM notably increased from 10 to 31%. Almost one-third (31%) of all patients dispensed the drugs in 2023 had no recorded diagnosis of either diabetes or obesity, compared to 8% in 2019.</p><p><strong>Conclusion: </strong>This study showed an increase in the dispensation of GLP-1 RA, with characteristics of patients changing towards a higher degree of off-label use. The effectiveness and safety of the increasing prescriptions warrant future studies.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A narrative review of the placebo effect: historical roots, current applications, and emerging insights.","authors":"Cagri Ozpolat, Yagmur Okcay, Kemal Gokhan Ulusoy, Oğuzhan Yildiz","doi":"10.1007/s00228-025-03818-6","DOIUrl":"https://doi.org/10.1007/s00228-025-03818-6","url":null,"abstract":"<p><strong>Purpose: </strong>Placebo is a term to define physiologically inactive compounds used in treatment that causes physical and emotional changes. The placebo effect, driven by expectation and conditioning, plays a significant role in various conditions like pain, depression, and Parkinson's disease, while the nocebo effect can hinder treatment outcomes. Understanding mechanisms such as neuromodulation and genetics has gained importance in modern medicine. This review aims to explore the clinical relevance of placebo responses, particularly in neuropsychiatric disorders, and their potential in personalized medicine. By integrating placebo research into healthcare, it highlights opportunities to enhance treatment efficacy, improve patient well-being, and reduce reliance on pharmacological interventions.</p><p><strong>Methods: </strong>A comprehensive literature search was conducted in PubMed, Scopus, and Google Scholar databases. Recent studies were reviewed to evaluate placebo effects, and the variability of the placebo response in neuropsychiatric disorders was summarized.</p><p><strong>Results: </strong>Placebo effects significantly impact treatment outcomes across various conditions, including Parkinson's disease, depression, pain syndromes, and epilepsy. The mechanisms involve neurobiological and psychological factors, with evidence suggesting that placebo interventions can modulate neurotransmitter activity and improve patient well-being.</p><p><strong>Conclusion: </strong>Integrating placebo research into clinical practice may enhance treatment outcomes, reduce drug dependency, and support personalized medicine by tailoring interventions to individual placebo responsiveness. Understanding placebo and nocebo mechanisms can optimize therapeutic strategies while minimizing unnecessary pharmacological treatments.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of surrogate endpoints in phase III randomized control trials of advanced hepatocellular carcinoma treated with immune checkpoint inhibitors.","authors":"Ke Jiang, Miaowen Liu, Xiao Zhao, Shutong Wang, Yunyan Ling, Liangliang Qiao, Jianfei Tu, Zhenwei Peng","doi":"10.1007/s00228-025-03820-y","DOIUrl":"https://doi.org/10.1007/s00228-025-03820-y","url":null,"abstract":"<p><strong>Purpose: </strong>Overall survival (OS) is recommended as a gold standard endpoint but has some limitations. We aimed to finding more effective surrogate endpoints for advanced hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs).</p><p><strong>Methods: </strong>Three online databases were searched for randomized control trials (RCTs) on HCC, published between January 2015 and July 2023, that evaluated ICIs and reported progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and OS. The correlation between the potential surrogate endpoints and OS was evaluated at the trial, arm, and patient levels. The prediction models were validated in single-arm or non-RCTs. Individual data were collected from a real-world (RW) cohort with advanced HCC underwent ICI monotherapy at three tertiary medical centers in China.</p><p><strong>Results: </strong>Ten RCTs (6023 participants) with 11 comparisons were included. PFS had a moderately significant association with OS (R² = 0.50, p = 0.014). ORR, DCR, and OS showed weak correlations. On limiting the analysis to ICI monotherapy studies, the correlations of OS with PFS became stronger (R² = 0.85, p = 0.02). The RW cohort also verified that PFS was closely related to OS when patient received with ICI monotherapy.</p><p><strong>Conclusion: </strong>PFS are recommended as surrogate markers in patients with advanced HCC treated with ICI monotherapy.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Era of surrogate endpoints and accelerated approvals: a comprehensive review on applicability, uncertainties, and challenges from regulatory, payer, and patient perspectives.","authors":"Rohini Sharma, Anamika Gulati, Kanwaljit Chopra","doi":"10.1007/s00228-025-03822-w","DOIUrl":"https://doi.org/10.1007/s00228-025-03822-w","url":null,"abstract":"<p><strong>Purpose: </strong>The regulatory landscape in rare diseases and oncology has evolved to address unmet medical needs by implementing expedited approval pathways. The US FDA's Accelerated Approval and the EMA's Conditional Marketing Authorization facilitate earlier patient access to therapies through reliance on surrogate endpoints derived from early-phase clinical trials. The review aims to provide a comprehensive review of the role and utilization of surrogate endpoints in accelerated drug approvals, highlighting their strengths, limitations, and the varying perspectives of stakeholders on their validity and utility.</p><p><strong>Methods: </strong>This article reviews existing literature and regulatory guidelines to assess the effectiveness and challenges associated with surrogate endpoints in expedited approval pathways. It also examines the post-approval commitment adherence required by regulatory bodies, exploring discrepancies among stakeholder perspectives.</p><p><strong>Results: </strong>Findings indicate that while surrogate endpoints enable faster market access, uncertainties remain regarding post-approval commitments and their consistency. Differences in stakeholder opinions also persist, reflecting varying levels of confidence in the validity and applicability of surrogate endpoints.</p><p><strong>Conclusion: </strong>Surrogate endpoints play a crucial role in accelerating drug approvals in areas with high unmet needs, yet challenges around post-approval commitments and stakeholder acceptance suggest the need for enhanced regulatory clarity and ongoing assessment of surrogate endpoint validity.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of colchicine on coagulation in patients with chronic coronary disease who use vitamin K antagonists.","authors":"Jeroen P A Houwen, Arief Lalmohamed, Jochem Zwaan, Toine C G Egberts, Michiel Duyvendak, Aernoud T L Fiolet, Arend Mosterd","doi":"10.1007/s00228-025-03815-9","DOIUrl":"https://doi.org/10.1007/s00228-025-03815-9","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Low-dose (0.5 mg/day) colchicine improves cardiovascular outcomes in patients with stable coronary disease. Around 10-15% of these patients simultaneously use anticoagulant therapy, including vitamin-K antagonists (VKAs). In vitro studies and case reports have described a possible interaction between colchicine and VKAs leading to increased INR, but controlled studies are lacking.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The aim of this study was to investigate if there is a drug-drug interaction between low-dose colchicine and VKAs in patients with chronic coronary disease.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study was a sub-analysis of the randomized low-dose colchicine for secondary prevention of cardiovascular disease 2 (LoDoCo2) trial. This placebo-controlled trial investigated efficacy of colchicine 0.5 mg once daily in patients with chronic coronary disease. For the current study, we included a selection of Dutch patients who concomitantly used a VKA. Following a 30 days open-label colchicine run-in phase, patients were randomized to colchicine or placebo. The primary outcome was the intra-patient difference in international normalized ratio (INR) during the first month after starting or stopping colchicine as compared to the preceding month. Secondary outcomes included changes in VKA daily dosage, assessed in the same pattern and before and after randomization, and time in therapeutic range (TTR), assessed before and after randomization to reflect long-term effects. INR measurements were part of routine clinical care.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In total, 73 patients were included (35 colchicine and 38 in the placebo group). No significant intra-patient change in INR was observed after starting colchicine during the open-label run-in phase (mean INR: 2.60 before vs. 2.67 during run-in, difference 0.07, 95% CI - 0.13 to 0.26; p = 0.50). Similarly, stopping colchicine treatment (i.e., randomization to placebo) did not significantly alter INR levels (mean INR: 2.70 during run-in vs. 2.81 after randomization, difference 0.11, 95% CI - 0.12 to 0.33; p = 0.34). The change in mean VKA daily dosage was - 0.01 mg (95% CI - 0.03 to 0.01; p = 0.35) when starting colchicine and - 0.01 mg (95% CI - 0.03 to 0.01; p = 0.41) when switching to placebo. TTR in patients allocated to active treatment was 65.8% in the year prior to the start of colchicine and 73.4% in the year after randomization to colchicine (change in TTR 7.56%, 95% CI - 0.14 to 15.26%; p = 0.05). Mean VKA dosage remained similar (change in VKA dosage of 0.01 mg; 95% CI - 0.11 to 0.13 mg; p = 0.84).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;No significant changes in INR, VKA dosage, or TTR in patients using VKAs after starting or stopping colchicine were observed. These results suggest that there is no need for additional INR monitoring beyond the standard of care when using low-dose colchicine, though further studies in larger populations would help to confirm this ","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative evaluation of the efficacy and safety of first-line systemic therapies for advanced hepatocellular carcinoma.","authors":"Xinrui Wang, Jihan Huang, Yixiao Liu, Lijuan Wu, Ruifen Cai, Qingshan Zheng, Lujin Li","doi":"10.1007/s00228-024-03797-0","DOIUrl":"10.1007/s00228-024-03797-0","url":null,"abstract":"<p><strong>Objectives: </strong>This study aimed to quantitatively evaluate the efficacy and safety of first-line systemic therapies for treating advanced hepatocellular carcinoma (aHCC).</p><p><strong>Methods: </strong>The study included clinical trials of first-line systemic therapies for aHCC since the approval of sorafenib in 2007. Hazard function models were used to describe changes in overall survival (OS) and progression-free survival (PFS) over time. Monte Carlo simulation was used to compare OS and PFS for different treatments, including sorafenib, antiangiogenic therapies (AATs) (except sorafenib), immune checkpoint inhibitor (ICI) monotherapy, AAT + targeted therapy, AAT + chemotherapy, AAT + ICIs, and ICIs + ICIs. Furthermore, the objective response rate (ORR) and incidence of grade ≥ 3 adverse events were analyzed.</p><p><strong>Results: </strong>Fifty studies comprising 12,918 participants were included. AAT + ICIs demonstrated a significant benefit in median OS (mOS), median PFS (mPFS), and ORR (20.5 [95% CI 17.5-24] months, 7.5 [95% CI 6.5-8.8] months, and 24% [95% CI 17%-30%], respectively). ICIs + ICIs and ICI monotherapy ranked second and third, respectively with an mOS of 20 (95% CI 18.5-21.5) months and 14.5 (95% CI 13.5-16) months, respectively. The OS, PFS, and ORR of patients treated with AAT, AAT + targeted therapy, and AAT + chemotherapy were similar to those of patients treated with sorafenib. A higher proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage C had a shorter OS. OS was associated with publication year, and PFS was associated with the proportion of patients with BCLC stage C. The incidence of grade ≥ 3 adverse events in the ICIs and ICIs + ICIs treatment groups was low.</p><p><strong>Conclusions: </strong>The study results provide valuable information from which to base rational clinical drug use and serves as a reliable external control for evaluating new treatments for aHCC.</p>","PeriodicalId":11857,"journal":{"name":"European Journal of Clinical Pharmacology","volume":" ","pages":"383-393"},"PeriodicalIF":2.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}