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Major Adverse Cardiac Events with Ondansetron: A Systematic Review. 昂丹司琼的主要心脏不良事件:系统回顾。
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-30 DOI: 10.1002/cpt.70189
Michael Cristian Garcia, Bhavya Gandhi, Faisal Quadri, Mahnoor Shahab, Kassie Rong, Genevieve Ramnarine, Ishleen Sudan, Sophia Zhang, Michelle Yu, Sara Mojdehi, Lawrence Mbuagbaw, Anne M Holbrook

Ondansetron frequently triggers medication safety alerts because of its listing as a 'known risk' QT interval-prolonging medication. We aimed to summarize literature on QT-prolongation-related major adverse cardiac events associated with ondansetron. We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central for randomized controlled trials comparing ondansetron to placebo in adults. Major adverse cardiac events (MACE) included death, nonfatal cardiac arrest, ventricular tachyarrhythmia including torsades de pointes, seizure, or syncope. Random-effects meta-analyses were performed with a treatment arm continuity correction for single- and double-zero event studies. We included 170 randomized trials (n = 23,421, 70.7% female, 48.3% aged >65), 119 trials (70.0%) involving surgical patients, and 77 (45.4%) including electrocardiograms. Mean follow-up was 10 days (SD: 21.8) (median: 1 day). Risk of bias was high for 11.8% of trials, and low for 28.8%. Only seven MACE (all deaths) were reported. Ondansetron was not associated with increased mortality (n = 23,421, RR: 1.03, 95% CI: 0.76-1.39, I2 = 0.0%), or arrhythmias. Lack of events precluded prespecified meta-analyses. Further research on QT-prolonging medications and their attributed adverse cardiac events and medication alert optimization is needed.

昂丹司琼经常触发药物安全警报,因为它被列为“已知风险”延长QT间期的药物。我们的目的是总结与昂丹司琼相关的qt延长相关的主要心脏不良事件的文献。我们检索了Medline, Embase, International Pharmaceutical Abstracts和Cochrane Central,查找了成人中比较昂丹司琼和安慰剂的随机对照试验。主要心脏不良事件(MACE)包括死亡、非致死性心脏骤停、室性心动过速(包括点扭转)、癫痫发作或晕厥。随机效应荟萃分析对单零事件和双零事件研究进行了治疗组连续性校正。我们纳入了170项随机试验(n = 23,421, 70.7%为女性,48.3%为年龄在65岁至65岁之间),119项试验(70.0%)涉及外科患者,77项试验(45.4%)涉及心电图。平均随访10天(SD: 21.8)(中位数:1天)。11.8%的试验偏倚风险高,28.8%的试验偏倚风险低。仅报告了7例MACE(全部死亡)。昂丹司琼与死亡率增加(n = 23,421, RR: 1.03, 95% CI: 0.76-1.39, I2 = 0.0%)或心律失常无关。缺乏事件排除了预先指定的荟萃分析。需要进一步研究延长qt的药物及其导致的心脏不良事件和药物警报优化。
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引用次数: 0
New Horizons for Clinical Pharmacology & Therapeutics: Global Outreach for Optimal Patient Outcomes 临床药理学和治疗学的新视野:最佳患者结果的全球推广。
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-29 DOI: 10.1002/cpt.70137
Karen Rowland Yeo
<p>As the incumbent Editor-in-Chief of <i>Clinical Pharmacology & Therapeutics</i>, my vision is to expand the journal’s global outreach and impact as well as showcase interdisciplinary collaborations and effective implementation strategies for therapeutics to improve patient outcomes across the globe. <i>CPT</i> will continue to publish world-class quantitative pharmacology in drug development and community settings and precision medicine in specific populations, especially the underserved, while broadening its scope to focus more on global health and social policies as well as patient perspectives. Furthermore, by bringing science to life using digital technology, we will strive to make CPT the leading forum for translating science into enhanced clinical care for patients.</p><p>Although clinical pharmacology is a global science, this is not always reflected in the literature. Thus, one of my priorities is to expand global outreach and authorship of <i>CPT</i>, particularly in low- to middle-income countries (LMICs). Having grown up in Zimbabwe and attended University in South Africa, I am very much aware of how rare these opportunities are (even nowadays) and the impact that they can have if made available. The success of the ASCPT LMIC Accelerator Program, which promotes diversity, equity and inclusion in global health forums and enables LMIC scholars to participate in ASCPT-related activities, is a testament to this! Furthermore, given the current geopolitical landscape, it is now more important than ever, to disseminate and act on challenges faced by clinical pharmacologists and patients across the world, especially in resource-limited settings. To that end, we have taken steps to ensure that our editorial team is more internationally representative (<b>Figure</b> 1, <b>Table</b> 1). The diverse interdisciplinary scientific expertise and regional perspectives across the team will enhance editorial decisions, better serve our authors and readers, as well as identify important underrepresented areas of research across the globe.</p><p>In this issue, several articles involving pharmacogenetic testing speak to my vision of addressing global and public health concerns. In the study by Ianni <i>et al</i>.<span><sup>1</sup></span> entitled: Insights into Patient-Level Exposure to Actionable Pharmacogenomic Medications in Australia Using a New National Pharmacogenomic Guideline, based on assessment of the use of 35 pharmacogenomic (PGx) medications, the authors discuss the advantages (medication efficacy/safety and cost-efficiency) of integrating PGx testing into routine practice weighed against the significant costs involved especially during the implementation stage. Ianni <i>et al</i>. conclude that “Future research should focus on scalable strategies for PGx implementation across diverse health care settings to optimize patient care globally.” In the multi-institutional prospective ACCOuNT trial, African American inpatients were genotyped a
作为《临床药理学与治疗学》杂志的现任主编,我的愿景是扩大该杂志的全球影响力,并展示跨学科合作和有效的治疗实施策略,以改善全球患者的治疗效果。CPT将继续发表药物开发和社区环境中的世界级定量药理学以及针对特定人群,特别是服务不足人群的精准医学,同时扩大其范围,更多地关注全球卫生和社会政策以及患者观点。此外,通过使用数字技术将科学带入生活,我们将努力使CPT成为将科学转化为增强患者临床护理的领先论坛。虽然临床药理学是一门全球性的科学,但这并不总是反映在文献中。因此,我的优先事项之一是扩大全球推广和撰写CPT,特别是在中低收入国家(LMICs)。我在津巴布韦长大,在南非上大学,我非常清楚这些机会是多么难得(即使在今天),以及如果它们能够得到,将会产生的影响。ASCPT LMIC加速器计划的成功,促进了全球卫生论坛的多样性、公平性和包容性,并使LMIC学者能够参与ASCPT相关活动,就是一个证明!此外,鉴于当前的地缘政治形势,传播和应对全球临床药理学家和患者面临的挑战,尤其是在资源有限的情况下,比以往任何时候都更加重要。为此,我们已采取措施确保我们的编辑团队更具国际代表性(图1,表1)。团队中跨学科的科学专业知识和区域视角将增强编辑决策,更好地服务于我们的作者和读者,并确定全球范围内重要的未被充分代表的研究领域。在本期中,几篇涉及药物遗传检测的文章与我对解决全球和公共卫生问题的看法一致。在Ianni等人的研究中,题为:使用新的国家药物基因组学指南了解澳大利亚患者对可操作的药物基因组学药物的暴露,基于对35种药物基因组学(PGx)药物使用的评估,作者讨论了将PGx测试纳入常规实践的优势(药物疗效/安全性和成本效益),并权衡了特别是在实施阶段所涉及的重大成本。Ianni等人得出结论:“未来的研究应侧重于在不同医疗环境中实施PGx的可扩展策略,以优化全球患者护理。”在多机构前瞻性ACCOuNT试验中,非裔美国住院患者进行了基因分型,PGx结果通过一个集成的、可扩展的药物基因组学临床决策支持(PGx CDS)系统提供,以告知处方虽然使用PGx CDS并没有改善基因一致性处方,但重要的是要强调住院护理团队使用该系统来确认处方决策。有趣的是,Bidoli等人3报告了一项转录组全关联研究(TWAS)的使用,该研究发现,在缺乏已知与TPMT和NUDT15相关的风险等位基因的急性淋巴母细胞白血病(ALL)患者中,GNAQ是一种与硫嘌呤耐受性相关的新基因。设想在临床实践中使用GNAQ作为6-巯基嘌呤剂量调整的潜在生物标志物,将允许准确给药,减少毒性,并最终改善ALL患者的预后。在上述所有场景中,涉及PGx评估的有效实施策略是关键。CPT将继续出版包括临床药物遗传学实施联盟(CPIC)在内的该领域专家的权威策略和指南。孕妇、哺乳期母亲及其婴儿仍然得不到充分的服务。因此,看到Gasparyan等人发表的文章反映了药物相关特征在预测母乳暴露中的效用,这是令人鼓舞的。此外,在题为“开发和完善妊娠结果验证妊娠算法确定性(ACE-IT)”的出版物中,Singh等人讨论了如何使用妊娠ACE-IT来确定妊娠/分娩结果的算法是否适合特定决策上下文的目的。与所有基于模型的工具一样,为了鼓励更广泛的接受和提高易用性,包括监管机构在内的最终用户需要了解操作方面及其解决临床问题的适用性,特别是在监管审查期间。 因此,禁毒署将继续鼓励包括美国食品和药物管理局在内的全球监管机构传播监管科学和指导,特别是在这些新兴领域和全球卫生政策方面。事实上,我们强调了药品和医疗器械管理局(PMDA)的一篇综述,描述了病理性近视治疗的评估,这代表了日益增长的全球公共卫生问题6,以及一篇讨论中国监管机构在解决当前与老年药物开发相关问题时的考虑的文章,标题恰当:银海啸处方:2005-2024年中国老年新药审批延迟与创新评价综合分析在前总编辑皮特·范德格拉夫的卓越领导下,即将离任的CPT编辑团队为我们奠定了坚实的基础,我们将继续发扬光大。我们将继续支持特刊和主题文集,关注药物公平等新兴议题,这是2026年亚太药品安全技术论坛会议的主题,也是我们将于2026年5月出版的完整主题刊的重要组成部分。此外,我们还将在2026年晚些时候发布另外两期主题杂志。其中第一个与新方法方法(NAMs)有关,FDA于2018年4月宣布计划将NAMs(例如,计算机模型)整合到其药物评估过程中,以取代对动物研究的需求。第二次会议将侧重于药物开发中的特定人群以及社区和全球卫生环境。我认为CPT不仅是一本期刊,也是一个合作平台;我们的目标是与ASCPT网络(定量药理学,转化和精密医学,发展,监管和结果)和社区合作,展示他们的科学实力和正在进行的倡议,并与我们的两个姊妹期刊CPT:药物计量学和系统药理学以及临床和转化科学建立更紧密的联系,以进一步增强ASCPT期刊家族的影响力。我们感谢所有读者一直以来的支持,感谢我们的审稿人,特别是编辑委员会成员,他们的辛勤工作和对保持审稿过程高标准的承诺。CPT将继续作为ASCPT的旗舰期刊,但作为一个更加全球化的平台,发表更多来自世界各地的文章。科学传播正在迅速变化;我们的目标是通过对话、数字平台、网络研讨会和社交媒体将科学带入生活。通过在线参与和扩大我们的知名度,我们将扩大CPT的外联性和相关性,并突出主要成果。此外,通过有效的沟通,我们可以使内容更容易获得,更重要的是与全定量临床药理学家、科学家、临床医生、政策制定者和患者相关(图2)。最后,作为《临床药理学》杂志的总编辑,我感到非常荣幸和荣幸。《临床药理学》杂志对快速发展的临床药理学领域起到了推动作用,对我个人的职业发展也起到了重要的作用。我对未来感到非常兴奋,并有机会与才华横溢的全球编辑团队一起帮助塑造这一学科和期刊的未来。我特别激动的是,我将与我们的副总编辑、20多年的好朋友兼同事Karthik Venkatakrishnan一起踏上这段旅程。我们的共同愿景很明确:确保每位患者无论其地理位置或社会经济地位如何,都能得到最好的治疗。只要齐心协力,我们就能改变现状,对患者(包括我们的家人和朋友)的生活产生影响。这项工作没有收到任何资金。作者声明对这项工作没有竞争利益。
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引用次数: 0
Clinical Safety of Extended Interval Dosing of Nivolumab in Patients with Melanoma. Nivolumab在黑色素瘤患者中延长间隔给药的临床安全性。
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-25 DOI: 10.1002/cpt.70182
Ruben Malmberg, Maaike M Hofman, Fatima Ashad, Alaa Daloul, Stefani Oosterveld, Edwin A Basak, Esther Oomen-de Hoop, Astrid A M van der Veldt, Arjen Joosse, Roelof W F van Leeuwen, Ron H J Mathijssen

Extended interval dosing regimens of immune checkpoint inhibitors have been implemented widely. However, their approval was mainly based on pharmacokinetic modeling and simulations. Consequently, comparative safety data of extended interval dosing regimens in a real-world setting are limited. This study compares grade ≥3 immune-related adverse events between standard and extended interval dosing of nivolumab in patients with melanoma and explores associated risk factors. This retrospective cohort study included patients with melanoma treated with nivolumab monotherapy from April 2016-September 2021 in the MULTOMAB study. Data on baseline characteristics and immune-related adverse events were collected from patients' electronic medical records with a maximum follow-up of 6 months. A total of 236 patients (125 metastatic and 111 adjuvant) were included, with 146 in the standard cohort and 90 in the extended interval cohort. Grade ≥3 immune-related adverse events occurred in 20 patients: 13 (8.9%) patients in the standard cohort and 7 (7.8%) in the extended interval cohort. No significant differences in grade ≥3 immune-related adverse events were observed between the two cohorts (P = 0.763). This study suggests that the risk of severe immune-related adverse events is comparable between both interval dosing regimens of nivolumab in patients with melanoma. Therefore, the extended interval dosing of nivolumab appears to be safe for application in standard care.

延长间隔给药方案免疫检查点抑制剂已广泛实施。然而,它们的批准主要基于药代动力学建模和模拟。因此,在现实环境中延长间隔给药方案的比较安全性数据是有限的。该研究比较了nivolumab标准剂量和延长间隔剂量对黑色素瘤患者≥3级免疫相关不良事件的影响,并探讨了相关的危险因素。这项回顾性队列研究包括2016年4月至2021年9月在MULTOMAB研究中接受纳武单抗单药治疗的黑色素瘤患者。基线特征和免疫相关不良事件的数据从患者的电子病历中收集,最长随访6个月。共纳入236例患者(125例转移性和111例辅助),其中146例属于标准队列,90例属于延长间隔队列。20例患者发生≥3级免疫相关不良事件:标准队列13例(8.9%),延长间隔队列7例(7.8%)。两组患者≥3级免疫相关不良事件发生率无显著差异(P = 0.763)。这项研究表明,在黑色素瘤患者中,两种间隔给药方案之间的严重免疫相关不良事件的风险是相当的。因此,延长纳武单抗间隔剂量在标准治疗中应用似乎是安全的。
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引用次数: 0
The Role for Clinical Translational Pharmacology in Advancing Pharmacoequity. 临床转化药理学在促进药物公平中的作用。
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-23 DOI: 10.1002/cpt.70181
Sonya Tang Girdwood, Sandra A G Visser

Advancing pharmacoequity is both a public health imperative and a scientific opportunity. While policy efforts have focused largely on post-approval issues like pricing, insurance, evidence-based prescribing practices, and pharmacy access, science offers powerful tools to address inequities much earlier. This perspective outlines how clinical translational pharmacology (CTP) is uniquely positioned as a scientific discipline to advance pharmacoequity through its principles, innovation, methods, and patient-centered applications across the discovery, development, regulation, and utilization (DDRU) continuum.

推进药物公平既是公共卫生的当务之急,也是科学的机遇。虽然政策努力主要集中在定价、保险、循证处方实践和药房获取等审批后问题上,但科学为更早地解决不平等问题提供了强有力的工具。这一观点概述了临床转化药理学(CTP)作为一门科学学科的独特定位,如何通过其原则、创新、方法和以患者为中心的应用,在发现、开发、监管和利用(DDRU)连续体中推进药物公平。
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引用次数: 0
PharmVar GeneFocus: NAT2-Genetic Variation and Updated Nomenclature. PharmVar GeneFocus: nat2遗传变异和更新的命名法。
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-23 DOI: 10.1002/cpt.70168
Georgia Papanikolaou, Estella S Poloni, José A G Agúndez, Raquel L F Teixeira, Erin C Boone, Adalberto Rezende Santos, Michelle Whirl-Carrillo, Katrin Sangkuhl, Teri E Klein, Mariam R Habil, Giannoulis Fakis, Rodney F Minchin, David W Hein, Sotiria Boukouvala, Andrea Gaedigk

The Pharmacogene Variation Consortium (PharmVar) provides nomenclature for the highly polymorphic human N-acetyltransferase 2 (NAT2) gene. NAT2 metabolizes several clinically used drugs including isoniazid, hydralazine, amifampridine, procainamide, and sulfonamides such as dapsone, and also some highly carcinogenic arylamines. Systematic nomenclature describing NAT2 variation is essential for pharmacogenetic testing, genotype interpretation, and translation to phenotype in research and clinical settings. This GeneFocus provides an overview of NAT2 variation and describes important changes to its star allele-based nomenclature that were made as it was transitioned to PharmVar in March 2024. We also highlight and discuss challenges regarding the characterization of allelic variation and determination of allele frequencies across world populations. The "new" NAT2 PharmVar nomenclature is utilized by ClinPGx (formerly PharmGKB) and the Clinical Pharmacogenetics Implementation Consortium (CPIC).

药物基因变异联盟(PharmVar)为高度多态性的人类n -乙酰基转移酶2 (NAT2)基因提供了命名法。NAT2代谢几种临床使用的药物,包括异烟肼、肼、阿米福定、普鲁卡因胺、磺胺类药物如氨苯砜,以及一些高致癌性的芳胺类药物。描述NAT2变异的系统命名对于药物遗传学检测、基因型解释以及研究和临床环境中的表型翻译至关重要。本GeneFocus提供了NAT2变异的概述,并描述了其基于星型等位基因的命名法在2024年3月过渡到PharmVar时所做的重要变化。我们还强调并讨论了关于等位基因变异特征和等位基因频率测定在世界人口中的挑战。ClinPGx(原PharmGKB)和临床药物遗传学实施联盟(CPIC)使用了“新”NAT2 PharmVar命名法。
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引用次数: 0
Minor Contribution of UGT1A1 Inhibition to Atazanavir-Related Bilirubin Elevation Supported by Conservative PBPK Modeling and Clinical Data 保守PBPK模型和临床数据支持UGT1A1抑制对阿扎那纳病毒相关胆红素升高的微小贡献
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-22 DOI: 10.1002/cpt.70185
Jin Dong, Pradeep Sharma, Rasha Emara, Derek Cheung, Weifeng Tang, Diansong Zhou, David W. Boulton, Mats Någård, Miki S. Park
<p>Drs Miners and Polasek highlighted challenges in the <i>in vitro</i> UGT and transporter assays for bilirubin.<span><sup>1</sup></span> We acknowledge these challenges, which had been considered in our physiologically based pharmacokinetic (PBPK) modeling.<span><sup>2</sup></span></p><p>We agree that there is a lack of confidence in the <i>in vitro</i>–<i>in vivo</i> extrapolation for UGTs and transporters, that is, optimized <i>in vitro</i> assays may still not represent <i>in vivo</i> conditions. Therefore, a middle-out modeling approach was employed. The <i>in vitro</i>/optimized parameters of relevant pathways underwent thorough validation, with most simulated results falling within 0.8–1.25-fold of observed clinical values.</p><p>It was suggested that the <i>K</i><sub>m</sub> value of UGT1A1-mediated unconjugated bilirubin (UB) metabolism could be >17-fold lower, whereas the <i>V</i><sub>max</sub> value could be >4-fold higher.<span><sup>1</sup></span> However, sensitivity analyses indicated that applying lower <i>K</i><sub>m</sub> or higher <i>V</i><sub>max</sub> values would predict smaller contribution of UGT1A1 inhibition to the total bilirubin (TB) elevation following atazanavir administration (<b>Figure</b> 1). This is because the faster the metabolism, the less impact by the same magnitude of inhibition. Also, OATP1B1/3 and UGT1A1 pathways function in tandem and compete for the role of rate-limiting step of UB elimination. When the metabolic rate of UGT1A1 increases, the hepatic uptake is further reinforced as the rate-limiting step. Additionally, our model did not underpredict the effect of UGT1A1 polymorphism on the baseline TB levels (<b>Figure</b> 1), suggesting a low risk of underpredicting the role of UGT1A1 in UB elimination.</p><p>Our original models were adjusted to further minimize the risk of underpredicting the contribution of UGT1A1 inhibition (<b>Figure</b> 1). However, UGT1A1 inhibition remains a minor contributor to the TB elevation in the adjusted simulations (<b>Figure</b> 1; UGT1A1 inhibition alone vs. all interaction pathways: atazanavir alone, 28% vs. 102%; atazanavir/ritonavir, 69% vs. 379%).</p><p>The conclusion reached from the PBPK modeling was also consistent with clinical data from bilirubin-sorafenib<span><sup>3</sup></span> (<b>Figure</b> 1) and dolutegravir-atazanavir<span><sup>4</sup></span> (<b>Figure</b> 1) interaction studies.<span><sup>2</sup></span> Notably, sorafenib is one of the strongest UGT1A1 inhibitors <i>in vitro</i> and clinically,<span><sup>5</sup></span> whereas it increased baseline TB levels by < 33%.<span><sup>3</sup></span> As atazanavir/ritonavir (300/100 mg q.d.) and sorafenib (400 mg b.d.) exhibit comparable UGT1A1 inhibition potential (<i>C</i><sub>ss,max,u</sub>/IC<sub>50,u</sub>, 2.77 vs. 2.18; <i>C</i><sub>ss,avg,u</sub>/IC<sub>50,u</sub>, 1.15 vs. 1.51),<span><sup>2</sup></span> UGT1A1 inhibition is unlikely to be the primary TB elevation mechanism.</p><p>We also a
miner博士和Polasek博士强调了胆红素体外UGT和转运体检测的挑战我们承认这些挑战,这在我们基于生理的药代动力学(PBPK)模型中已经被考虑过。我们同意,对ugt和转运体的体内外推断缺乏信心,也就是说,优化的体外测定可能仍然不能代表体内条件。因此,采用中间出建模方法。对相关途径的体外/优化参数进行了充分的验证,大多数模拟结果与临床观察值相差0.8 - 1.25倍。结果表明,ugt1a1介导的非偶联胆红素代谢Km值可降低17倍,而Vmax值可提高4倍然而,敏感性分析表明,应用较低的Km或较高的Vmax值可以预测阿扎那韦给药后UGT1A1抑制对总胆红素(TB)升高的贡献较小(图1)。这是因为新陈代谢越快,同样程度的抑制作用的影响就越小。此外,OATP1B1/3和UGT1A1通路协同作用,并竞争UB消除的限速步骤。当UGT1A1代谢率增加时,肝脏摄取作为限速步骤进一步加强。此外,我们的模型并没有低估UGT1A1多态性对基线结核水平的影响(图1),这表明低估UGT1A1在UB消除中的作用的风险很低。我们对原始模型进行了调整,以进一步降低低估UGT1A1抑制作用的风险(图1)。然而,在调整后的模拟中,UGT1A1抑制仍然是结核病升高的次要因素(图1;UGT1A1单独抑制与所有相互作用途径:阿扎那韦单独抑制,28%对102%;阿扎那韦/利托那韦,69%对379%)。PBPK模型得出的结论也与胆红素-索拉非尼3(图1)和dolutegravir-atazanavir4(图1)相互作用研究的临床数据一致值得注意的是,索拉非尼是体外和临床中最强的UGT1A1抑制剂之一,但它使基线结核水平提高了33%由于阿扎那韦/利托那韦(每日300/100 mg)和索拉非尼(每日400 mg)具有相当的UGT1A1抑制潜力(Css,max,u/IC50,u, 2.77 vs. 2.18; Css,avg,u/IC50,u, 1.15 vs. 1.51),2 UGT1A1抑制不太可能是结核病升高的主要机制。我们也同意瑞非尼和索拉非尼作为高亲和力UGT1A1抑制剂的低药物-药物相互作用风险(AUC比不大于2.25)1表明,ugt作为高容量酶,与低或高亲和力抑制剂的相互作用风险较低。这项研究是由阿斯利康公司资助的。p.s.、w.t.、d.z.、d.w.b.和M.N.是阿斯利康的雇员,他们可能持有公司的股票所有权、期权和/或权益。所有其他作者声明对这项工作没有竞争利益。
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引用次数: 0
Lower Dose-Normalized Tacrolimus Exposure in CYP3A5*6 vs. *3 Loss-of-Function Allele Carriers: A Longitudinal Retrospective Real-World Study in Kidney Transplant Recipients. 低剂量标准化他克莫司暴露于CYP3A5*6与*3功能丧失等位基因携带者:肾移植受者的纵向回顾性现实世界研究
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-22 DOI: 10.1002/cpt.70162
Amar D Levens, Dirk Jan A R Moes, Yanick Boer, Aiko P J de Vries, Dorottya K de Vries, Danny van der Helm, Soufian Meziyerh, Dave L Roelen, Stefan Böhringer, Teun Van Gelder, Jesse J Swen

Pharmacogenomic research has historically focused on individuals of European ancestry, leading to the underrepresentation of genetic variants common in non-European populations. This bias is exemplified by CYP3A5*6, a functionally consequential variant common in individuals of African ancestry (MAF: 11-19%) but virtually absent in Europeans (MAF: 0.15%). We conducted a retrospective, longitudinal cohort study using real-world data from 1,461 adult kidney transplant recipients across 67 countries, analyzing 4,293 dose-normalized 24-hour area-under-the-curve (AUC0-24) measurements of tacrolimus. Patients with CYP3A5*1/*1 were excluded. Linear mixed-effects models (LME) were used to assess the association between CYP3A5*6 carriage and tacrolimus exposure, adjusting for clinical factors and ancestry using both HLA-based principal components and country of birth. CYP3A5*6 carriers had a 17% lower dose-normalized AUC0-24 than CYP3A5*3 carriers (P = 0.015). Sensitivity analyses using dose-normalized trough concentrations (C0) confirmed these findings, with a 20% lower exposure in CYP3A5*6 carriers (P = 0.011). An interval-based analysis demonstrated persistently lower tacrolimus exposure across the first post-transplant year. All CYP3A5*6-containing genotypes showed significantly lower dose-normalized AUC0-24 compared to CYP3A5*3/*3, the most common genotype in European populations, with the largest reductions observed in CYP3A5*1/*6 (-39%; P < 0.001) and CYP3A5*3/*6 (-18%; P = 0.006). African origin, defined by country of birth, was independently associated with a 23% higher AUC0-24 (P < 0.001). This is the first study to demonstrate a differential effect on tacrolimus exposure between the CYP3A5*6 and CYP3A5*3 loss-of-function alleles. Our results may help bridge the ethnicity gap, advance the applicability of pharmacogenomic findings, and promote health equity.

药物基因组学研究历来集中在欧洲血统的个体上,导致非欧洲人群中常见的遗传变异代表性不足。这种偏见的例证是CYP3A5*6,这是一种在非洲血统个体中常见的功能相关变异(MAF: 11-19%),但在欧洲人中几乎不存在(MAF: 0.15%)。我们进行了一项回顾性、纵向队列研究,使用来自67个国家的1461名成年肾移植受者的真实数据,分析了4293个他克莫司剂量标准化的24小时曲线下面积(AUC0-24)测量值。排除CYP3A5*1/*1的患者。使用线性混合效应模型(LME)评估CYP3A5*6携带与他克莫司暴露之间的关系,使用基于hla的主成分和出生国家调整临床因素和血统。CYP3A5*6携带者的剂量标准化AUC0-24比CYP3A5*3携带者低17% (P = 0.015)。使用剂量标准化谷浓度(C0)的敏感性分析证实了这些发现,CYP3A5*6携带者的暴露降低了20% (P = 0.011)。一项基于间隔的分析表明,在移植后的第一年,他克莫司暴露量持续较低。与欧洲人群中最常见的基因型CYP3A5*3/*3相比,所有含有CYP3A5*6的基因型的AUC0-24均显著降低,其中CYP3A5*1/*6的AUC0-24降低幅度最大(-39%
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引用次数: 0
Mechanistic Population Pharmacokinetic-Pharmacodynamic Model of the Tau-Targeted Antibody Posdinemab in Healthy Participants and Participants with Alzheimer's Disease. tau靶向抗体Posdinemab在健康和阿尔茨海默病患者体内的群体药动学-药效学模型
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-22 DOI: 10.1002/cpt.70173
Carlos Pérez-Ruixo, Lingjue Li, Wendy R Galpern, Juan José Perez-Ruixo

Disrupted homeostasis and transneuronal spread of hyperphosphorylated Tau protein (pTau) are hypothesized to be key pathogenic drivers of Alzheimer's disease (AD). Posdinemab (JNJ-63733657), a humanized IgG1/kappa monoclonal antibody that targets phosphorylated Tau protein at amino acid 217 (p217+tau), is currently in clinical development for the treatment of AD. In a first-in-human Phase 1 study (NCT03375697), posdinemab was well tolerated at doses up to 60 mg/kg, demonstrated linear pharmacokinetics (PK) in serum, and induced dose-dependent reductions in p217+tau levels in cerebrospinal fluid (CSF). The objective of the current analysis was to develop a mechanism-based population pharmacokinetic-pharmacodynamic (popPK-PD) model to guide the Phase 2 (Auτonomy) dose selection of posdinemab in participants with AD using the Phase 1 data from 69 adults. A two-compartment model was selected, which successfully described the available clinical PK-PD data and demonstrated that posdinemab PK in serum is linear, dose-proportional, and time-independent. Suppression of free p217+tau in CSF was used to reflect free antibody available to bind tau seeds in interstitial fluid (ISF). The PK-PD model-based simulations for fixed intravenous doses of 1,000 mg and 3,000 mg every 4 weeks predicted >90% reduction in tau seeds in ISF by Day 391 and Day 154, respectively, following treatment initiation. This model provides a physiologically relevant simulation-framework to investigate the impact of various posdinemab dose levels on PK-PD profiles, thereby supporting the clinical trial design of the Auτonomy study (NCT04619420).

过度磷酸化的Tau蛋白(pTau)被认为是阿尔茨海默病(AD)的关键致病因素。Posdinemab (JNJ-63733657)是一种人源化IgG1/kappa单克隆抗体,靶向磷酸化的Tau蛋白氨基酸217 (p217+ Tau),目前正处于临床开发阶段,用于治疗AD。在一项首次人体i期研究(NCT03375697)中,posdinemab在高达60mg /kg的剂量下具有良好的耐受性,在血清中显示出线性药代动力学(PK),并诱导脑脊液(CSF)中p217+tau水平的剂量依赖性降低。当前分析的目的是建立一个基于机制的人群药代动力学-药效学(popPK-PD)模型,以指导波替那单抗在AD患者中的二期(auτ经济学)剂量选择,该模型使用来自69名成人的一期数据。我们选择了一个双室模型,该模型成功地描述了可用的临床PK- pd数据,并证明了泊替那单抗在血清中的PK是线性的、剂量正比的和时间无关的。通过抑制脑脊液中游离p217+tau来反映可结合间质液(ISF)中tau种子的游离抗体。基于PK-PD模型的模拟显示,在治疗开始后的第391天和154天,每4周静脉注射1000毫克和3000毫克的固定剂量,ISF中的tau种子分别减少了约90%。该模型提供了一个生理学相关的模拟框架,以研究不同泊替那单抗剂量水平对PK-PD谱的影响,从而支持auτ经济学研究(NCT04619420)的临床试验设计。
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引用次数: 0
Risk of Malignancies and Major Adverse Cardiovascular Events Related to JAK Inhibitors in Rheumatoid Arthritis: A Meta-Analysis 类风湿关节炎患者与JAK抑制剂相关的恶性肿瘤风险和主要不良心血管事件:一项荟萃分析
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-22 DOI: 10.1002/cpt.70146
Hongmei Duan, Chao Jiang, Binglun Zhang, Hefan Meng, Weizheng Zhou, Wei Yan, Tianlong Jiang

This meta-analysis evaluated the risk of malignancies and major adverse cardiovascular events (MACE) associated with the use of JAK inhibitors in patients with RA through a comprehensive meta-analysis of available clinical trials. A systematic search was conducted in PubMed, EMBASE, and Web of Science from inception to February 7, 2025, to identify relevant clinical trials. Data on malignancies and MACE incidence were extracted, and pooled risk ratios (RR) were calculated using a random-effects model. A total of 18 studies (N = 111,260) met the inclusion criteria. JAK inhibitors were associated with a significantly increased risk of malignancies excluding NMSC (RR = 1.30, 95%CI: 1.05, 1.60; P = 0.016), NMSC (RR = 1.54, 95%CI: 1.23, 1.93; P < 0.01), overall malignancies (RR = 1.53, 95%CI: 1.18, 2.00; P = 0.002), lung cancer (RR = 1.52, 95%CI: 1.11, 2.08; P = 0.009), lymphoma (RR = 3.69, 95%CI: 1.19, 11.42; P = 0.024), non-small cell lung cancer (RR = 1.70, 95%CI: 1.01, 2.86; P = 0.047), cutaneous squamous cell carcinoma (RR = 2.30, 95%CI: 1.44, 3.65; P < 0.01), and thyroid cancer (RR = 7.51, 95%CI: 1.39, 40.74; P = 0.019). In contrast, JAK inhibitors did not significantly alter the risk of MACE (RR = 0.75, 95%CI: 0.38, 1.45; P = 0.390), venous thromboembolism (VTE) (RR = 1.52, 95%CI: 0.90, 2.56; P = 0.117), or deep vein thrombosis (DVT) (RR = 1.77, 95%CI: 0.84, 3.34; P = 0.079). Trial sequential analysis (TSA) confirmed data adequacy, and meta-regression indicated that sample size, treatment duration, and patient age did not influence outcomes. JAK inhibitors are associated with an elevated risk of malignancies but do not significantly affect MACE, VTE, or DVT risk in RA patients. Further large-scale post-marketing surveillance is warranted to refine the safety profile of JAK inhibitors in RA management.

本荟萃分析通过对现有临床试验的综合荟萃分析,评估了与RA患者使用JAK抑制剂相关的恶性肿瘤和主要不良心血管事件(MACE)的风险。系统检索PubMed, EMBASE和Web of Science从成立到2025年2月7日,以确定相关临床试验。提取恶性肿瘤和MACE发生率的数据,并使用随机效应模型计算合并风险比(RR)。共有18项研究(N = 111,260)符合纳入标准。除NMSC外,JAK抑制剂与恶性肿瘤风险显著增加相关(RR = 1.30, 95%CI: 1.05, 1.60; P = 0.016), NMSC (RR = 1.54, 95%CI: 1.23, 1.93
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引用次数: 0
Risk of Acute Kidney Injury Associated With Nephrotoxic Burden in Hospitalized Patients: A Scoping Review. 住院患者肾毒性负担相关的急性肾损伤风险:范围综述
IF 5.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-12-21 DOI: 10.1002/cpt.70169
Wafa Alatawi, Jessica L Wallace, Dhakrit Rungkitwattanakul, Britney A Stottlemyer, Tiffany L Tran, Melanie Manis Reida, Sandra L Kane-Gill

Limited evidence exists synthesizing the risk of acute kidney injury (AKI) associated with the concomitant administration of multiple nephrotoxic drugs, and even less examining the concept of nephrotoxic burden. The objective of this scoping review was to (1) identify definitions of nephrotoxic burden; (2) methods used to quantify (use of calculations) nephrotoxic burden; and (3) determine the association between nephrotoxic burden and AKI risk. Additionally, we assessed studies reporting the risk of AKI with the concurrent use of three or more nephrotoxic drugs. Following PRISMA guidelines, a comprehensive literature search was conducted. Observational studies in hospitalized patients were included if they assessed nephrotoxic burden or the risk of AKI with concurrent nephrotoxic drug use. Sixteen studies met the inclusion criteria. Four studies assessed nephrotoxic burden, two of which defined and quantified it, and two additional studies adopted those definitions to evaluate associations with AKI. All four reported a significant relationship between increased nephrotoxic burden and AKI risk. Twelve studies evaluated the likelihood of AKI with concurrent administration of three or more nephrotoxic drugs, with reported odds ratios ranging from 1.15 to 3.18 per additional drug. The deleterious effects of concomitant exposure to three or more nephrotoxins on the kidney are evident, stressing a need to take conscious action from a clinician and institutional perspective in the attempt to prevent AKI. Future research should incorporate drug-specific weighting and consistent reporting standards to improve nephrotoxic burden assessment and guide clinical decision-making to reduce AKI.

综合急性肾损伤(AKI)风险与同时使用多种肾毒性药物相关的证据有限,对肾毒性负担概念的研究就更少了。本综述的目的是:(1)确定肾毒性负担的定义;(2)量化(使用计算)肾毒性负担的方法;(3)确定肾毒性负担与AKI风险之间的关系。此外,我们评估了报告同时使用三种或更多种肾毒性药物的AKI风险的研究。按照PRISMA指南,进行了全面的文献检索。住院患者的观察性研究如果评估肾毒性负担或AKI并发肾毒性药物的风险,则纳入其中。16项研究符合纳入标准。四项研究评估了肾毒性负担,其中两项对其进行了定义和量化,另外两项研究采用了这些定义来评估与AKI的关系。所有四例均报告了肾毒性负担增加与AKI风险之间的显著关系。12项研究评估了同时服用三种或三种以上肾毒性药物发生AKI的可能性,每增加一种药物的优势比从1.15到3.18不等。同时暴露于三种或三种以上肾毒素对肾脏的有害影响是显而易见的,强调需要从临床医生和机构的角度采取有意识的行动来预防AKI。未来的研究应纳入药物特异性加权和一致的报告标准,以改善肾毒性负担评估和指导临床决策,以减少AKI。
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引用次数: 0
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Clinical Pharmacology & Therapeutics
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