Clinical Pharmacology & Therapeutics最新文献

{"title":"Inhibition of OATP1B1/3 Rather Than UGT1A1 May Be the Major Cause of the Bilirubin Elevation After Atazanavir Administration.","authors":"Jin Dong, Pradeep Sharma, Rasha Emara, Derek Cheung, Weifeng Tang, Diansong Zhou, David W Boulton, Mats Någård, Miki S Park","doi":"10.1002/cpt.3529","DOIUrl":"https://doi.org/10.1002/cpt.3529","url":null,"abstract":"<p><p>Atazanavir has been reported to increase total serum bilirubin level up to ninefold. It is widely believed that the observed total bilirubin elevation is primarily due to UGT1A1 inhibition. However, UGT enzymes are well-known as a low-affinity and high-capacity system, and the observed drug-drug interaction mediated by UGTs is usually less than twofold. There were discrepancies in the explanation of total bilirubin elevation due to UGT1A1 inhibition alone, suggesting the contribution of other mechanism(s) to the interaction. As atazanavir is a potent OATP1B1/3 inhibitor and the hepatic uptake of both unconjugated and conjugated bilirubin are mediated by OATP1B1/3, these transporters could be involved in the bilirubin-atazanavir interaction. To better understand the roles of UGT1A1 and OATP1B1/3 in this interaction, it would be useful to characterize the contribution of each individual pathway to the interaction. As multiple compounds, pathways, and potentially UGT1A1 polymorphism are involved, a thorough physiologically-based pharmacokinetic (PBPK) analysis was utilized to integrate the information from various relevant in vitro and clinical studies to quantitatively estimate the contribution of UGT1A1 and OATP1B1/3 inhibition to the interaction between bilirubin and atazanavir. The PBPK analysis indicated that UGT1A1 inhibition plays a modest role in bilirubin and atazanavir interaction contributing less than 33%. The results also suggested that unconjugated bilirubin is less sensitive than raltegravir upon UGT1A1 inhibition, therefore, unconjugated bilirubin may not be a useful endogenous biomarker for UGT1A1 inhibition. The analysis demonstrated that the metabolism of unconjugated bilirubin shares common features of other UGT enzyme-mediated reactions.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk of Hypoglycemia Associated with Concomitant Use of Insulin Secretagogues and ACE Inhibitors in Adults with Type 2 Diabetes: A Systematic Review.","authors":"Patricia Y Chu, Emma K Edmondson, James H Flory, Jing Huang, Sean Hennessy","doi":"10.1002/cpt.3530","DOIUrl":"10.1002/cpt.3530","url":null,"abstract":"<p><p>Insulin secretagogues and angiotensin-converting enzyme inhibitors (ACEIs) are commonly co-prescribed for patients with type 2 diabetes (T2D). Case reports suggesting that co-administration of insulin secretagogues with ACEIs is associated with an increased risk of serious hypoglycemia have led to warnings regarding a drug-drug interaction in widely used drug compendia. However, subsequent studies have had inconsistent results. We performed a systematic review to evaluate the evidence that concomitant use of ACEIs and insulin secretagogues increases the risk of serious hypoglycemia. MEDLINE/PubMed and Embase were searched from inception to July 2023 for studies evaluating adults with T2D treated with insulin secretagogues, such as sulfonylureas or meglitinides, and exposed to an ACEI. The primary outcome was serious hypoglycemia. A literature search yielded 472 papers, of which five met the inclusion criteria. The heterogeneity of the studies precluded meta-analysis. Two studies using multiple methods to address bias found no association between hypoglycemia and concomitant use of ACEI and insulin secretagogues. Three studies found potential associations, but only one was statistically significant; these studies were at serious or critical risk of bias due to potential confounding from lack of adjustment for renal dysfunction. The higher quality studies found no association between the concomitant use of insulin secretagogues with ACEI and hypoglycemia. Drug compendia and electronic health records should consider updating and removing alerts warning of a drug-drug interaction between insulin secretagogues as a class and ACEIs.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population Pharmacokinetic/Pharmacodynamic and Exposure-Response Modeling Analyses of Sotatercept in Healthy Participants and Patients with Pulmonary Arterial Hypertension.","authors":"Sihem Ait-Oudhia, David Jaworowicz, Ziheng Hu, Mitali Gaurav, Heather Barcomb, Shuai Hu, Sébastien Bihorel, Budda Balasubrahmanyam, Bipin Mistry, Janethe de Oliveira Pena, Larissa Wenning, Ferdous Gheyas","doi":"10.1002/cpt.3524","DOIUrl":"https://doi.org/10.1002/cpt.3524","url":null,"abstract":"<p><p>Sotatercept is a breakthrough, first-in-class biologic, recently approved by the Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (PAH). Exposure-response (E-R) analyses and pharmacokinetic/pharmacodynamic (PK/PD) modeling were performed for sotatercept after intravenous and subcutaneous (SC) administrations. Clinical endpoints included 6-minute walk distance (6MWD), pulmonary vascular resistance (PVR), and probability of N-terminal pro-B natriuretic peptide (NT-proBNP) concentrations < 300 pg/mL for efficacy, and hemoglobin (Hgb) for safety from two Phase 1 studies, two Phase 2 studies, and one Phase 3 study. E-R models using nonlinear mixed effect modeling approach were developed for 6MWD and PVR, while Cox proportional hazards model and semi-mechanistic PK/PD model were used for NT-proBNP and Hgb. Covariate analyses were conducted to identify significant predictors of variability for each of these clinical endpoints. Modeling results showed that increasing sotatercept average concentration (C_avg) at week 24 is associated with increased predicted 6MWD, increased probability of NT-proBNP concentration < 300 pg/mL, decreased predicted PVR, and increased Hgb which was clinically manageable. All these responses approached their corresponding plateaus at a C_avg range associated with the dose of 0.7 mg/kg Q3W SC. Statistically relevant covariates included age and iron supplementation which slightly increased Hgb-mediated effect for 6MWD, PAH disease duration, and baseline therapy infusion with prostacyclin for PVR, and WHO functional class for NT-proBNP. The magnitudes of the impact of these covariates are not clinically meaningful. Taken together, these results support an appropriate benefit-risk profile for the FDA-approved target dose for sotatercept of 0.7 mg/kg Q3W SC.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Leveraging QSP Models for MIPD: A Case Study for Warfarin/INR”","authors":"","doi":"10.1002/cpt.3517","DOIUrl":"10.1002/cpt.3517","url":null,"abstract":"<p>Falkenhagen, U., Cavallari, L.H., Duarte, J.D., Kloft, C., Schmidt, S. and Huisinga, W. (2024), Leveraging QSP models for MIPD: a case study for Warfarin/INR. <i>Clin Pharmacol Ther</i>, 116: 795–806. https://doi.org/10.1002/cpt.3274.</p><p>In the published version of the above article, the authors noticed that one of the funding details was missing and it has been listed below.</p><p>“The research of WH has been partially funded by the Deutsche Forschungsgemeinschaft (DFG) – Project-ID 318763901 – SFB1294.”</p><p>We apologize for this error.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":"117 2","pages":"598"},"PeriodicalIF":6.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cpt.3517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of the Monoclonal Antibody, Sotrovimab, in Healthy Participants Following IM Administration at Different Injection Sites.","authors":"Asma El-Zailik, Jennifer Sager, Yasmin Sánchez-Pearson, Sergio Parra, Jennifer Moore, Prosenjit Sarkar, Alicia Aylott, Qianwen Wang, Melissa Aldinger, Chad Garner, Erik Mogalian, Andrew Skingsley, Amanda Peppercorn, Maribel Reyes","doi":"10.1002/cpt.3515","DOIUrl":"https://doi.org/10.1002/cpt.3515","url":null,"abstract":"<p><p>Sotrovimab is a recombinant human monoclonal antibody for the early treatment of mild-to-moderate COVID- 19. A phase I, open-label, randomized, parallel-group study was conducted to investigate the pharmacokinetics, relative bioavailability, safety, and tolerability of two concentrations of sotrovimab administered intramuscularly at different injection sites in healthy volunteers. The study consisted of three parts (A, B, and C) and the pharmacokinetic results from Part A are reported herein. In Part A, participants were randomized in a 2:2:1:1 ratio to a 500 mg dose of 62.5 mg/mL sotrovimab administered into dorsogluteal muscle, or 100 mg/mL sotrovimab administered into dorsogluteal, anterolateral thigh, or deltoid muscles. Formulation concentration did not impact exposure following dorsogluteal administration; the point estimates (90% confidence interval [CI]) of the geometric mean ratios (GMRs) of area under the curve (AUC)_inf and maximum serum concentration (C_max) for dorsogluteal administration of 100 mg/mL vs. 62.5 mg/mL intramuscular sotrovimab were 0.95 (0.86-1.05) and 1.14 (1.02-1.27), respectively. However, the administration of 100 mg/mL sotrovimab in thigh or deltoid resulted in increased exposure relative to gluteal injections; the point estimates (90% CI) of the GMRs for 100 mg/mL intramuscular sotrovimab administered into thigh or deltoid muscles vs. 100 mg/mL administered dorsogluteally were 1.63 (1.46-1.83) and 1.50 (1.34-1.67) for AUC_inf, and 1.82 (1.60-2.08) and 1.49 (1.31-1.69) for C_max, respectively. Notably, thigh and deltoid administration also resulted in lower variability in key pharmacokinetic parameters such as AUC, C_max, apparent clearance and volume of distribution, and earlier achievement of C_max, than dorsogluteal intramuscular administration of sotrovimab.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the Clinical Development Trajectory of Cell and Gene Therapy Products.","authors":"Magdi Elsallab, Michelle Ouvina, Andrea Arfe, Florence T Bourgeois","doi":"10.1002/cpt.3512","DOIUrl":"https://doi.org/10.1002/cpt.3512","url":null,"abstract":"<p><p>While cell and gene therapies (CGTs) have emerged as promising modalities to treat conditions with limited therapeutic options, their unconventional development is fraught with uncertainty, rendering them high-risk assets for many pharmaceutical companies. Here, we assess the clinical development trajectories of CGT products by estimating probabilities of successful clinical trial phase transitions and the likelihood of achieving regulatory approval. We included all CGT products entering clinical development from 1993 to 2023 and intended for marketing in the United States, Europe, Japan, Canada, and Switzerland. Associations between product success and characteristics were investigated. In sub-analyses, we examined the clinical trajectories of two promising product types, chimeric antigen receptor T (CAR T) cell therapies and adeno-associated viral (AAV) vector-based gene therapies. We identified 995 CGT products corresponding to 1,961 development programs. A total of 44 CGTs secured at least one regulatory approval, corresponding to an overall likelihood of approval of 5.3% (95% CI 4.0-6.9). Development programs with an orphan designation had a higher likelihood of approval than those without (9.4%, 95% CI 6.6-13.3 vs. 3.2%, 95% CI 2.0-4.9), while programs for oncology indications had a lower likelihood of approval compared to those for non-oncology indications (3.2%, 95% CI 1.6-5.1 vs. 8.0%, 95% CI 5.7-11.1). CAR T cells and AAV gene therapies had a similar overall likelihood of approval of 13.6% (95% CI 7.3, 23.9) and 13.6% (95% CI 6.4, 26.7), respectively. In conclusion, CGT products have a low overall likelihood of approval with variability based on orphan status, therapeutic area, and product type.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Barriers and Facilitators for Bringing Model-Informed Precision Dosing to the Patient's Bedside: A Systematic Review.","authors":"Anna Caroline Dibbets, Charlotte Koldeweij, Esra P Osinga, Hubertina C J Scheepers, Saskia N de Wildt","doi":"10.1002/cpt.3510","DOIUrl":"https://doi.org/10.1002/cpt.3510","url":null,"abstract":"<p><p>Model-informed precision dosing (MIPD) utilizes mathematical models to predict optimal medication doses for a specific patient or patient population. However, the factors influencing the implementation of MIPD have not been fully elucidated, hindering its widespread use in clinical practice. A systematic review was conducted in PubMed from inception to December 2022, aiming to identify barriers and facilitators for the implementation of MIPD into patient care. Articles with a focus on implementation of MIPD were eligible for this review. After screening titles and abstracts, full articles investigating the clinical implementation of MIPD were included for data extraction. Of 790 records identified, 15 publications were included. A total of 72 barriers and facilitators across seven categories were extracted through a hybrid thematic analysis. Barriers comprised limited data for model validation, unclear regulatory pathways for model endorsement and additional drug level measurements required for certain types of MIPD. Facilitators encompassed the development of user-friendly MIPD tools continuously updated based on user feedback and data. Collaborative efforts among diverse stakeholders for model validation and implementation, along with education of end-users, may promote the utilization of MIPD in patient care. Despite ongoing challenges, this systematic review revealed various strategies to facilitate the clinical implementation of MIPD.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of Efficacy Evidence for Approvals of Novel Drugs in China Between 2018 and 2022.","authors":"Yang Xu, Xinyu Li, Qixiang Guo, Qi Chen, Mengfan Su, Xuenong Zhang, Yue Yang","doi":"10.1002/cpt.3511","DOIUrl":"https://doi.org/10.1002/cpt.3511","url":null,"abstract":"<p><p>After the reform of China's drug review and approval system, there has been a notable increase in the number of novel drugs approved. This cross-sectional study aimed to assess the characteristics of efficacy evidence for novel drugs approved in China. This study included 240 novel drugs approved by the NMPA for 256 indications between 2018 and 2022. Compared with imported original drugs, the trials of innovative drugs were less frequently subjected to be randomized (67.7% vs. 80.3%; P = 0.01) and placebo (32.3% vs. 45.5%; P = 0.02), and more likely to use external control and surrogate endpoint. There was a significant difference in all features between pivotal trials of drugs with conditional approval and regular approval. Among imported original drugs, the drug for urgent clinical needs used placebo control (58.1% vs. 39.5%; P < 0.001) and scale endpoint more frequently, whereas rare disease drugs seldom utilized active control. The median number of subjects across all pivotal trial intervention groups was 197 (IQR, 86-379), with a median trial duration of 6.0 months (IQR, 3.0-12.7). The median number of pivotal trials per indication for imported original drugs was higher than that of innovative drugs (2.0 [IQR, 1.0-3.0] vs. 1.0 [IQR, 1.0-1.0]; P < 0.001). The innovative drugs typically had either one pivotal trial or one trial plus supportive evidence, both of which accounted for 79.8% of all indications of innovative drugs. The most commonly applied types of supportive evidence across all indications were additional studies and mechanistic evidence. This study illustrated the characteristics of the quality and quantity of efficacy evidence. Special regulatory programs and special drug catalogs offered the agency regulatory flexibility with respect to evidentiary requirements.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, Pharmacokinetics, and Pharmacodynamics of a First-in-Class ClC-1 Inhibitor to Enhance Muscle Excitability: Phase I Randomized Controlled Trial.","authors":"Titia Q Ruijs, Catherine M K E de Cuba, Jules A A C Heuberger, John Hutchison, Jane Bold, Thomas S Grønnebæk, Klaus G Jensen, Eva Chin, Jorge A Quiroz, Thomas K Petersen, Peter Flagstad, Marieke L de Kam, Michiel J van Esdonk, Erica Klaassen, Robert J Doll, Ingrid W Koopmans, Annika A de Goede, Linda B S Aulin, Thomas H Pedersen, Geert Jan Groeneveld","doi":"10.1002/cpt.3516","DOIUrl":"https://doi.org/10.1002/cpt.3516","url":null,"abstract":"<p><p>NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects. Single-ascending doses (50-1,600 mg) were administered in a (partial) cross-over design; multiple-ascending doses (200-600 mg q.d.; 400 mg b.i.d.) were administered in a parallel design. Differences in pharmacokinetics between males/females and fed/fasted states were evaluated. Pharmacodynamic effects were evaluated using muscle velocity recovery cycles (MVRC) and analyzed using mixed-effects modeling. NMD670 was generally safe and well-tolerated in healthy subjects, with the only dose-related adverse event being myotonia occurring at the highest dose levels tested (single dose of 1,200, and 1,600 mg). Moreover, NMD670 significantly increased the following MVRC parameters after a single dose of 1,200 mg compared with placebo: early supernormality (estimated difference (ED) 2.04; 95% confidence interval (CI) 0.379, 3.70; P = 0.0242); early supernormality after 5 conditioning stimuli (ED 2.51; 95%CI 0.599, 4.41; P = 0.0177); supernormality at 20 ms (ED 2.78; 95%CI 1.377, 4.181; P = 0.0021). Importantly, the results of this study indicate pharmacological target engagement at well-tolerated dose levels in healthy subjects; firstly, because myotonia was an expected exaggerated on-target pharmacological effect, and secondly, because the effects on MVRC indicate increased muscle cell excitability. This study in healthy subjects indicates proof-of-mechanism and provides a solid base for translation to patients with neuromuscular diseases.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142798715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Background Factors Contributing to Safety Warning Discordance in the Initial Labeling of New Drugs in Japan, the United States, and the European Union.","authors":"Koichi Fukuda, Mamoru Narukawa","doi":"10.1002/cpt.3518","DOIUrl":"https://doi.org/10.1002/cpt.3518","url":null,"abstract":"<p><p>Drug labels summarize essential safety information for healthcare professionals and patients. However, studies have reported a discordance of safety information in drug labeling among countries/regions. We aimed to identify the characteristics of adverse events associated with discordant safety warnings during the initial labeling of new drugs approved at approximately the same time in Japan, the United States, and the European Union. Safety warning discordance/concordance between two countries/regions and the explanatory variables were assessed using multivariable logistic regression. The safety warning concordance rate was 71.0% (152/214) for the United States and the European Union, 59.5% (135/227) for Japan and the United States, and 64.3% (144/224) for Japan and the European Union. A significant association with discordant safety warnings was revealed for \"adverse event rate\" and \"warning status in a similar drug\" between the United States and the European Union; \"adverse event rate,\" \"adverse event included in important medical event list,\" and \"warning status in a similar drug\" between Japan and the United States; and \"adverse event included in important medical event list\" and \"warning status in a similar drug\" between Japan and the European Union. Clarifying and publicizing the reasons for safety warnings, along with an awareness of the factors associated with the discordance identified in this study, will help healthcare professionals, patients, marketing authorization holders, and regulatory authorities around the world share the background of country/region-specific warnings, reducing the possibility of confusion among them due to the discrepancies.</p>","PeriodicalId":153,"journal":{"name":"Clinical Pharmacology & Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}