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Cerebral Ischemia Protection After Aneurysmal Subarachnoid Hemorrhage: CSF Nimodipine Levels After Intravenous Versus Oral Nimodipine Administration. 动脉瘤性蛛网膜下腔出血后的脑缺血保护:静脉注射与口服尼莫地平后的脑脊液尼莫地平水平。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-19 DOI: 10.1002/cpt.3499
Miriam M Moser, Karl Rössler, Dorian Hirschmann, Leon Gramss, Ammar Tahir, Walter Plöchl, Johannes Herta, Andrea Reinprecht, Markus Zeitlinger, Arthur Hosmann

There is accumulating evidence that cerebrospinal fluid (CSF) concentrations of nimodipine correlate with long-term outcome of patients after subarachnoidal hemorrhage (aSAH) by impeding cerebral ischemia. However, pharmacological data on simultaneous serum vs. CSF and intraparenchymal nimodipine values are rarely reported in larger patient groups. Nimodipine concentrations were determined in plasma, CSF, and cerebral interstitial fluid (ISF), at steady state after oral (6 × 60 mg/day) and intravenous (0.5, 1, 1.5 and 2 mg/h) administrations in 10 patients after aSAH. Area under the concentration time curve (AUC0-24) for intravenous nimodipine was highest at an infusion rate of 2 mg/h in plasma (1335.87 ± 591.09 mg*h/L), followed by CSF (39.53 ± 23.07 mg*h/L), resulting in an overall CSF penetration ratio of 3.8% (±1.5) (AUCCSF/AUCplasma). In contrast, nimodipine levels were significantly lower in both plasma (AUC0-24 298.32 ± 206.52 mg*h/L) and CSF (AUC0-24 34.8 ± 16.56 mg*h/L) after oral administration. In cerebral ISF, low amounts of nimodipine were detectable in only 4 patients at an infusion rate of 1.5 and 2 mg/h as well as following oral administration. We found significantly higher CSF nimodipine levels in patients during intravenous compared to oral administration. In contrast, only low amounts of nimodipine were detected in the ISF after both oral and intravenous administration. Our findings strongly suggest that the main clinical nimodipine effect of impeding life threatening cerebral ischemia is mediated through significant higher CSF levels after intravenous administration, more likely effective than oral administration.

越来越多的证据表明,脑脊液(CSF)中尼莫地平的浓度通过抑制脑缺血与蛛网膜下腔出血(aSAH)患者的长期预后相关。然而,在较大的患者群体中,很少有关于血清与脑脊液和脑实质内尼莫地平同时浓度值的药理学数据报道。本研究测定了 10 名SAH 患者口服(6 × 60 毫克/天)和静脉注射(0.5、1、1.5 和 2 毫克/小时)后血浆、CSF 和脑间质(ISF)中尼莫地平的稳态浓度。静脉注射尼莫地平的浓度时间曲线下面积(AUC0-24)在输注速率为 2 mg/h 时血浆中最高(1335.87 ± 591.09 mg*h/L),其次是脑脊液(39.53 ± 23.07 mg*h/L),因此总体脑脊液渗透率为 3.8% (±1.5) (AUCCSF/AUCplasma)。相比之下,口服尼莫地平后,血浆(AUC0-24 298.32 ± 206.52 mg*h/L)和脑脊液(AUC0-24 34.8 ± 16.56 mg*h/L)中的尼莫地平水平均显著降低。在脑ISF中,只有4名患者在输注速率为1.5和2 mg/h以及口服给药后检测到低量尼莫地平。我们发现,与口服给药相比,静脉给药患者的脑脊液尼莫地平水平明显更高。相比之下,口服和静脉给药后在脑脊液中只检测到少量尼莫地平。我们的研究结果有力地表明,尼莫地平阻碍危及生命的脑缺血的主要临床效果是通过静脉给药后显著较高的脑脊液水平来介导的,这比口服给药更有可能有效。
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引用次数: 0
Contemporary Use of β-Blockers in Heart Failure Patients With and Without Atrial Fibrillation: A Nationwide Database Analysis. 有心房颤动和无心房颤动的心力衰竭患者目前使用β-受体阻滞剂的情况:全国数据库分析。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-18 DOI: 10.1002/cpt.3496
Michikazu Nakai, Yoshitaka Iwanaga, Koshiro Kanaoka, Yoko Sumita, Yuichi Nishioka, Tomoya Myojin, Katsuki Okada, Tatsuya Noda, Tomoaki Imamura, Yoshihiro Miyamoto

Evidence of the effectiveness of β-blockers in heart failure (HF) and atrial fibrillation (AF) in a contemporary cohort is controversial. This study investigated the association between the use of β-blockers and prognosis in hospitalized HF patients with and without AF in Japan. Patients hospitalized with the first episode of acute HF were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan between April 2014 and March 2021. Associations of β-blocker use and prognosis were compared by propensity score matching among the AF or non-AF group. A mixed-effects survival model was used, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Among 428,650 patients discharged with HF in 4,433 hospitals, 175,174 (40.9%) were ≥ 85 years old, 151,873 (35.4%) had complicated AF, and 236,457 (55.2%) were β-blocker users. In a matched AF group, β-blocker use was associated with a lower composite outcome of all-cause mortality or HF rehospitalization (HR [95% CI], 0.95 [0.93-0.97]). A similar result was obtained in a matched non-AF group (0.95 [0.94-0.96]). In addition, the HRs in patients aged ≥ 85 years and female patients were 1.00 [0.98-1.02] and 1.01 [0.98-1.03] in the AF group and 1.03 [1.01-1.05] and 0.98 [0.97-1.00] in the non-AF group, respectively. The favorable prognostic associations of β-blocker use were observed regardless of AF in patients across a broad spectrum of HF in a superaged society.

在当代人群中,β-受体阻滞剂对心力衰竭(HF)和心房颤动(AF)的有效性证据尚存在争议。本研究调查了日本有房颤和无房颤的住院高血压患者使用β-受体阻滞剂与预后之间的关系。研究人员从2014年4月至2021年3月期间的日本全国健康保险索赔和特定健康检查数据库中找到了首次急性心房颤动住院患者。通过倾向得分匹配法比较了心房颤动组和非心房颤动组患者使用β受体阻滞剂与预后的关系。研究采用了混合效应生存模型,并计算了危险比 (HR) 和 95% 置信区间 (CI)。在 4,433 家医院的 428,650 名因心房颤动出院的患者中,175,174 人(40.9%)年龄≥ 85 岁,151,873 人(35.4%)患有复杂性心房颤动,236,457 人(55.2%)使用过 β 受体阻滞剂。在匹配的心房颤动组中,β-受体阻滞剂的使用与较低的全因死亡率或高血压再住院综合结果相关(HR [95%CI],0.95 [0.93-0.97])。在匹配的非房颤组中也得到了类似的结果(0.95 [0.94-0.96])。此外,心房颤动组中年龄≥ 85 岁的患者和女性患者的 HR 分别为 1.00 [0.98-1.02] 和 1.01 [0.98-1.03],非心房颤动组中的 HR 分别为 1.03 [1.01-1.05] 和 0.98 [0.97-1.00]。在一个超高龄社会中,无论房颤与否,使用β受体阻滞剂都能为各种类型的心房颤动患者带来有利的预后。
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引用次数: 0
Infection Risk Associated with High-Efficacy Disease-Modifying Agents in Multiple Sclerosis: A Retrospective Cohort Study. 多发性硬化症患者使用高效改变病情药物的感染风险:一项回顾性队列研究
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-15 DOI: 10.1002/cpt.3492
Jieni Li, George J Hutton, Tyler J Varisco, Ying Lin, Ekere J Essien, Rajender R Aparasu

In patients with multiple sclerosis (MS), infections represent a significant concern, particularly given the immunomodulatory effects of disease-modifying agents (DMAs). High-efficacy DMAs (heDMAs) play a pivotal role in delaying MS progression, yet their use also raises concerns regarding the risk of infection. This study aimed to compare the infection risk with the use of heDMA and moderate-efficacy disease-modifying agents (meDMAs) in MS patients. This retrospective cohort study involved adult (18-64 years) MS patients with incident DMA use based on the 2015-2019 MarketScan Commercial Claims and Encounters Database. Patients initiating heDMAs (natalizumab, alemtuzumab, and ocrelizumab) or meDMAs (interferon beta-1a, interferon beta-1b, fingolimod, teriflunomide, dimethyl fumarate, and glatiramer acetate) were included. The outcomes of interest were comparative risk of overall infection, serious infection, and frequently reported types of infection. Adjusted hazard ratios (aHR) were estimated in inverse probability treatment weighting (IPTW) based on Cox proportional hazard models. Among 10,003 eligible incident DMA users, 22.92% of patients initiated heDMAs. The IPTW-CPH model revealed that patients with heDMAs were associated with a higher risk of serious infection (aHR: 1.24, 95% confidence interval (CI): 1.06-1.44) and urinary tract infection (UTI; aHR: 1.21, 95% CI: 1.14-1.30). Sensitivity analyses with different follow-up periods yielded consistent findings with the main analyses. In MS, heDMAs were associated with a greater risk of serious infection and UTI compared with meDMAs. These findings suggest the need to carefully monitor and manage the infection risk to optimize the use of heDMAs in MS.

对于多发性硬化症(MS)患者来说,感染是一个重大问题,尤其是考虑到疾病改变药物(DMAs)的免疫调节作用。高效DMAs(heDMAs)在延缓多发性硬化症进展方面发挥着关键作用,但其使用也引发了对感染风险的担忧。本研究旨在比较多发性硬化症患者使用heDMA和中效疾病改变药物(meDMA)的感染风险。这项回顾性队列研究涉及成年(18-64 岁)多发性硬化症患者,根据 2015-2019 年 MarketScan 商业索赔和会诊数据库,他们都曾使用过 DMA。研究纳入了开始使用 heDMAs(纳他珠单抗、阿来珠单抗和奥克雷珠单抗)或 meDMAs(β-1a 干扰素、β-1b 干扰素、芬戈莫德、特利氟胺、富马酸二甲酯和醋酸格拉替雷)的患者。关注的结果是总体感染、严重感染和经常报告的感染类型的比较风险。调整后的危险比(aHR)是根据 Cox 比例危险模型以反概率治疗加权法(IPTW)估算的。在 10,003 名符合条件的 DMA 使用者中,22.92% 的患者开始使用 heDMA。IPTW-CPH 模型显示,使用 heDMAs 的患者发生严重感染(aHR:1.24,95% 置信区间 (CI):1.06-1.44)和尿路感染(UTI;aHR:1.21,95% CI:1.14-1.30)的风险较高。不同随访期的敏感性分析结果与主要分析结果一致。在 MS 中,与 meDMA 相比,heDMA 与更高的严重感染和 UTI 风险相关。这些研究结果表明,需要仔细监测和管理感染风险,以优化 heDMAs 在 MS 中的使用。
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引用次数: 0
Correction to Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions. 校正有效利用 RWD 进行外部控制:关于监管和 HTA 决策的系统文献综述》。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-15 DOI: 10.1002/cpt.3453
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引用次数: 0
Exposure-Response Analyses of Sacituzumab Govitecan Efficacy and Safety in Patients With Metastatic Triple-Negative Breast Cancer. 萨妥珠单抗戈维替康对转移性三阴性乳腺癌患者疗效和安全性的暴露-反应分析
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-14 DOI: 10.1002/cpt.3495
Abhishek G Sathe, Paul M Diderichsen, Floris Fauchet, See-Chun Phan, Sandhya Girish, Ahmed A Othman

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in metastatic setting). Exposure-response (E-R) relationships between SG exposure and efficacy and safety outcomes were characterized in 277 patients with mTNBC using data from the phase I/II IMMU-132-01 and phase III ASCENT (IMMU-132-05) studies. Evaluated endpoints included complete response (CR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety endpoints (individual first worst grade of select adverse events (AEs)). E-R analyses were also conducted for time to first dose reduction or delay. Patients received SG at 8 or 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle. Average SG-related serum exposure over the treatment duration (until the event) was consistently the most significant exposure metric correlated with efficacy and safety endpoints. Higher average concentration over the treatment duration for SG (CAVGSG) was the best predictor of CR and ORR. The model-predicted proportions of patients with CR and ORR at 10 mg/kg were 4.26% and 32.6%, respectively. Higher CAVG for total antibody was the best predictor of OS and PFS. The model-predicted probability of OS at 12 months at median lactate dehydrogenase (227 IU/L) was 53%. The probability of grade ≥1 evaluated AEs and the risk of dose reductions and delays significantly increased with increasing CAVGSG. The model-predicted proportions of patients with any-grade AEs were 35.9%, 67.4%, 64.7%, and 67.1% for vomiting, diarrhea, nausea, and neutropenia, respectively (10 mg/kg dose group). Neutropenia was the only evaluated AE for which CAVGSG was significantly associated with grade ≥3 events. The clinically meaningful efficacy and manageable safety achieved with SG 10 mg/kg on days 1 and 8 of every 21-day cycle dosing regimen supports the appropriateness of this clinical dosage in patients with mTNBC.

萨妥珠单抗戈维替康(SG)是一种Trop-2导向的抗体药物共轭物,已被批准用于既往接受过≥2次全身治疗(转移性情况下≥1次)的转移性三阴性乳腺癌(mTNBC)患者。利用I/II期IMMU-132-01和III期ASCENT (IMMU-132-05)研究的数据,对277例mTNBC患者的SG暴露与疗效和安全性结果之间的暴露-反应(E-R)关系进行了描述。评估的终点包括完全应答 (CR)、客观应答率 (ORR)、无进展生存期 (PFS)、总生存期 (OS) 和安全性终点(选择性不良事件 (AE) 的最严重等级)。此外,还对首次减量或延迟服药时间进行了E-R分析。患者在21天周期的第1天和第8天静脉注射8或10毫克/千克的SG。在治疗期间(直至发生事件),与 SG 相关的血清平均暴露量一直是与疗效和安全性终点相关的最重要暴露量指标。治疗期间 SG 平均浓度越高(CAVGSG),预测 CR 和 ORR 的效果就越好。模型预测的 CR 和 ORR 患者比例在 10 mg/kg 时分别为 4.26% 和 32.6%。较高的总抗体 CAVG 是预测 OS 和 PFS 的最佳指标。乳酸脱氢酶中位数(227 IU/L)时,模型预测的12个月OS概率为53%。随着 CAVGSG 的增加,出现≥1 级评价 AE 的概率以及剂量减少和延迟的风险显著增加。模型预测的呕吐、腹泻、恶心和中性粒细胞减少等任何等级AEs患者比例分别为35.9%、67.4%、64.7%和67.1%(10 mg/kg剂量组)。中性粒细胞减少是 CAVGSG 与≥3 级事件显著相关的唯一 AE。在每21天周期给药方案的第1天和第8天使用10毫克/千克的SG,取得了有临床意义的疗效和可控的安全性,这证明这一临床剂量适用于mTNBC患者。
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引用次数: 0
HIGHLIGHTED ARTICLES 重点文章
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-14 DOI: 10.1002/cpt.3476
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引用次数: 0
Therapeutic Orphan No More: Role for Clinical Pharmacology and Translational Science in Developing Therapeutics for Rare and Neglected Diseases 不再是治疗孤儿:临床药理学和转化科学在开发罕见和被忽视疾病治疗药物中的作用。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-14 DOI: 10.1002/cpt.3474
Anuradha Ramamoorthy, Islam Younis, Ya-Feng Wen, Mai Mehanna, Kathleen M. Giacomini, Piet H. van der Graaf
<p>Rare disease (a disease that affects fewer than 1 in about 2,000 people<span><sup>1</sup></span>) and neglected disease (an infectious disease that is present in lower income countries) have very limited therapeutic options and can be considered as “therapeutic orphans.” Collectively, rare and neglected diseases are estimated to affect nearly 2 billion people worldwide – about 300 million people are estimated to be affected by rare diseases and 1.7 billion by neglected tropical diseases.<span><sup>2, 3</sup></span> However, it is reported that only <5% of rare diseases and a limited number of neglected diseases have therapeutic options available.<span><sup>4, 5</sup></span> That is, even though one in four people globally are affected by these diseases, very limited therapeutic options exist for these patients. In this special issue, we focus on rare diseases to highlight challenges and opportunities in developing therapies for these diseases and showcase the current and future role of clinical pharmacology and translational sciences in addressing the challenges and taking advantage of the opportunities. Additionally, the American Society for Clinical Pharmacology & Therapeutics (ASCPT) 2024 Annual Meeting Award and State-of-Art lectures summarized in this issue also highlight the challenges and opportunities in developing effective therapies for the neglected diseases (e.g., tropical diseases including tuberculosis) and neglected populations (e.g., pregnant women or breastfeeding mothers). Our intention for this special issue of <i>Clinical Pharmacology & Therapeutics</i> (<i>CPT</i>) is that we can all collectively learn from these examples and experiences to accelerate drug development for these therapeutic orphans (<b>Figure</b> 1).</p><p>There are a number of challenges in developing therapies for rare diseases. Because each rare disease afflicts only a small number of patients, the market size is relatively limited, and consequently, developing drugs for many of these diseases may not be considered as being commercially attractive. Additionally, most rare diseases are poorly understood because limited longitudinal natural history data are available, and consequently, more information on disease etiology, pathogenesis, genotype-to-phenotype correlation, disease progression, and outcome is needed. Furthermore, the small patient population size can lead to difficulties in enrolling sufficient numbers of patients in clinical trials and in generating adequate data to determine the benefit–risk profile of the drug. Compounding these challenges, there may be a lack of well-established biomarkers or animal models that can be leveraged during drug development. In sum, insufficient commercial interest and inadequate scientific research make it challenging to develop effective therapeutics for rare diseases.</p><p>Recognizing some of these challenges and limitations, several regulatory agencies and public-private partnerships have focuse
22 临床药理学在正确掌握剂量方面也发挥着重要作用,尤其是在最近一期 CPT 特刊所讨论的精准药物时代。23 虽然 "Optimus 项目 "旨在改革癌症疗法的剂量优化和剂量选择模式,但正确掌握剂量对于肿瘤和非肿瘤罕见病同样至关重要。在本期杂志中,Ahmed 等人24 描述了为新型和新兴疗法(包括酶替代疗法、细胞和基因疗法以及寡核苷酸疗法)选择适当剂量时所面临的一些挑战和机遇。他们讨论了如何整合各种来源的数据,包括动物模型、体内外药理学研究、基于模型的预测和真实世界数据,以选择合适的剂量。特别是,建模和模拟方法有助于克服罕见病药物开发中的某些挑战,因为这些基于暴露、生物和药物统计的模型可以整合临床前和临床来源的数据。Mitra 等人25 讨论了新型定量方法在加速罕见病药物开发中的应用,如定量系统药理学(QSP)、疾病进展建模、人工智能(AI)、机器学习(ML)和临床试验模拟。Neves-Zaph 和 Kaddi26 特别关注 QSP,讨论了 QSP 在罕见病药物开发中的应用现状,包括生成实际患者的虚拟数字双胞胎、从机理上模拟罕见病的疾病进展以及考虑表型异质性。他们介绍了如何开发 QSP 虚拟人群,使其比罕见病临床试验中经常登记的人群(代表轻度、中度和重度表型)更加多样化,并支持对代表性不足的患者亚群的治疗效果进行预测。此外,Hamdan 等人20 还展示了如何通过分析 ARCA 登记册中的自然病史数据来更有效地描述疾病进展特征,从而更好地为试验设计提供信息。要让儿童参与临床试验,一般的期望是潜在的治疗方法应能提供直接获益的前景。这种独特的环境(即罕见病患儿)凸显了利用临床药理学原理和我们所掌握的工具的重要性。我们可以整合儿童与成人疾病相似性(如有)以及两类人群生理差异的知识,评估研究药物对罕见病儿童的安全性和有效性。在本期中,Krishna 等人28 总结了制药行业在开发儿科罕见病药物方面的经验,重点关注生物标记物和替代终点、统计和开发注意事项、建模和模拟以及公私合作伙伴关系。他们还强调了与使用主协议、端到端定量整合以及共享试验水平安慰剂数据以了解疾病进展相关的机遇。读者可参阅本白皮书和 Ahmed 等人的白皮书24 ,进一步了解儿科罕见病疗法开发中的挑战和机遇。在本期的一篇 "视角 "文章中,Attipoe 介绍了 "被忽视疾病药物倡议"(DNDi)的作用和贡献。在一篇小型评论中,Waitt 等人30 对 2024 年多洛雷斯-肖克利奖的演讲内容进行了扩展,讨论了将育龄妇女、孕妇和哺乳期妇女纳入临床试验(包括药代动力学研究)的伦理必要性,前提是预期该患者亚群将使用该药物。他们强调了当地社区参与和能力建设的重要性。Mulubwa 和 Chibale31 强调有必要在建立模型的同时考虑到通常不参与生物医学研究的人群,以便设计出适合特定人群的剂量。他们介绍了如何利用非洲人的体外肝脏亚细胞分馏数据,纳入非洲基因变异信息(包括考虑人工智能预测的非洲流行药物代谢基因变异频率,以考虑整个非洲大陆的药物遗传多样性),并纳入体外 Mtb 药物代谢动力学数据,以促进结核病治疗方法的个性化,结核病是一种被忽视的疾病,有大量医疗需求未得到满足。 罕见病和被忽视疾病患者往往面临漫长、艰难和昂贵的诊断和治疗过程。17、19 学术机构、生物制药公司、患者、患者权益组织、监管机构和医疗服务提供者都需要联合起来,共同推进这些治疗孤儿的治疗工作(图 1)。应对罕见病和被忽视疾病的挑战需要多个学科的共同努力。我们呼吁临床药理学和转化科学界跨部门、跨学科合作,共同改变罕见病和被忽视疾病的面貌,为全球数百万患者带来希望。Inc 可能拥有默克公司的股票。公司的股票。文雅锋是吉利德科学公司的员工,可能拥有吉利德科学公司的股票。Anuradha Ramamoorthy目前是ASCPT董事会成员。本文仅代表作者个人观点,不应被视为代表 FDA 的观点。
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引用次数: 0
Hyponatremia Associated with the Use of Common Antidepressants in the All of Us Research Program. 与 "我们所有人 "研究项目中使用普通抗抑郁药有关的低钠血症。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-14 DOI: 10.1002/cpt.3484
Huan Mo, Yamna Channa, Tracey M Ferrara, Bennett J Waxse, David J Schlueter, Tam C Tran, Anas H Awan, Slavina B Goleva, Ariel Williams, Anav Babbar, Onajia Stubblefield, Jacob M Keaton, Eric A Larson, Russell A Wilke, Joshua C Denny

Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.

选择性血清素再摄取抑制剂(SSRI)、血清素-去甲肾上腺素再摄取抑制剂(SNRI)和去甲肾上腺素-多巴胺再摄取抑制剂(NRI)类抗抑郁药可通过抗利尿激素分泌不当综合征(SIADH)引起低钠血症。本研究以 "我们所有人研究计划"(All of Us Research Program)中的一项回顾性观察队列研究为参照,评估了与常用处方 SSRIs(氟西汀、帕罗西汀、舍曲林、西酞普兰、艾司西酞普兰)、SNRIs(度洛西汀、文拉法辛)和 NRIs(安非他酮)以及奥美拉唑相关的低钠血症的不同风险。研究对象包括接受过八种常见抗抑郁药中任何一种单药治疗的患者,每种药物都被视为一个独立的治疗组,并以开始日期为索引。事件定义为首次出现低血浆钠测量值或低钠血症或 SIADH 的临床诊断记录。未发生事件的患者在最后一次测量血浆钠时被剔除。共有 17,439 人接受了八种抗抑郁药中的一种作为单一疗法。在抗抑郁药物治疗组中,低钠血症的总发生率在头30天为0.87%,头3年为10.5%。与舍曲林相比,度洛西汀(危险比 [HR] = 1.37 [1.19-1.58])和艾司西酞普兰(HR = 1.16 [1.01-1.33])的低钠血症总风险最高,而安非他酮(HR = 0.83 [0.73-0.94])和帕罗西汀(HR = 0.78 [0.65-0.93])的风险最低。在对合并症和多重用药进行调整后,风险保持不变。这些信息有助于指导医疗服务提供者管理患者及其服用普通抗抑郁药时发生低钠血症的风险。
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引用次数: 0
The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID-19 Patients: A Physiologically Based Pharmacokinetic Modeling Study. 地塞米松和泼尼松对 COVID-19 患者阿哌沙班和利伐沙班暴露的影响:基于生理学的药代动力学模型研究。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-13 DOI: 10.1002/cpt.3491
Jean Terrier, Kenza Abouir, Frederic Gaspar, Youssef Daali, Caroline Flora Samer

Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen-dependent COVID-19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P-glycoprotein (P-gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P-gp, such as direct oral anticoagulants (DOAC). Currently, there is limited robust evidence to support a clinically significant interaction between DEX and DOAC. Using physiologically based pharmacokinetic modeling (PBPK), we investigated the impact of DEX administered in the context of SARS-CoV-2 infection on the pharmacokinetics of apixaban (APX) and rivaroxaban (RVX). After validating the induction effect of the DEX compound on two CYP3A4 substrates using the limited available studies, we optimized the compound in a COVID-19 patient population, where significantly higher DEX plasma concentrations were observed compared to healthy volunteers. Our PBPK-based PK simulations showed a 20% decrease in the AUC of APX and RVX in a worst-case scenario and when DEX was administered at 6 mg PO for 10 days. This finding confirms the limited clinical data currently available and supports the use of APX and RVX with DEX in COVID-19 patients at low-risk for thrombo-embolism. In addition, our results suggest that prednisone (PRED), when used at an equipotent dose, could serve as a viable alternative to DEX, given its less pronounced induction effect on APX and RVX. Further research is needed to validate these findings and to explore the clinical implications of using PRED in place of DEX in such scenarios.

地塞米松(DEX)是目前治疗氧依赖性 COVID-19 患者的首选药物。据观察,地塞米松主要在体外诱导 CYP3A 和编码 P 糖蛋白(P-gp)的 ABCB1 基因的表达。这引起了人们对地塞米松与 CYP3A 和 P-gp 底物(如直接口服抗凝剂 (DOAC))之间潜在相互作用的担忧。目前,支持 DEX 与 DOAC 之间存在临床显著相互作用的有力证据有限。我们利用生理学药代动力学模型(PBPK)研究了在感染SARS-CoV-2时服用DEX对阿哌沙班(APX)和利伐沙班(RVX)药代动力学的影响。在利用有限的现有研究验证了 DEX 复合物对两种 CYP3A4 底物的诱导作用后,我们在 COVID-19 患者群体中对该复合物进行了优化,观察到 DEX 的血浆浓度明显高于健康志愿者。我们基于 PBPK 的 PK 模拟显示,在最坏的情况下,DEX 的 AUC 和 RVX 降低了 20%,并且以 6 毫克 PO 持续给药 10 天。这一结果证实了目前有限的临床数据,并支持在血栓栓塞低风险的 COVID-19 患者中使用 APX 和 RVX 与 DEX。此外,我们的研究结果表明,泼尼松(PRED)对 APX 和 RVX 的诱导作用不明显,因此在使用同等剂量时可作为 DEX 的可行替代品。还需要进一步的研究来验证这些发现,并探讨在这种情况下使用 PRED 替代 DEX 的临床意义。
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引用次数: 0
A Systematic Review of the Costs of Drug-Associated Acute Kidney Injury and Potential Cost Savings with Nephrotoxin Stewardship Prevention Strategies. 药物相关急性肾损伤的成本及肾毒素管理预防策略的潜在成本节约系统回顾。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-11-13 DOI: 10.1002/cpt.3493
Britney A Stottlemyer, Tiffany Tran, Kangho Suh, Sandra L Kane-Gill

There is a scarcity of information related to the financial impact of acute kidney injury (AKI), and even more so the economics of drug-associated AKI (D-AKI). Our goal was to provide a comprehensive summary of the economic burden of D-AKI by evaluating the costs of D-AKI compared to not developing AKI and cost savings associated with nephrotoxin stewardship approaches. Following the PRISMA guidelines, a literature search was conducted using PubMed to identify articles from database inception through November 2023. The main outcomes included AKI incidence, resource use, and cost of nephrotoxin stewardship programs/D-AKI event or no event. Key findings were summarized based on whether the study compared the cost of D-AKI vs. no AKI or identified potential cost savings associated with a nephrotoxin stewardship method to prevent D-AKI or worsening D-AKI. All costs were adjusted to USD2023. Twenty-five studies met the inclusion criteria. Eight studies compared the cost of D-AKI to no AKI. Total admission costs of patients who developed D-AKI ranged from $47,696 to $173,569. Nineteen studies implemented nephrotoxin stewardship with 12 substituting a less nephrotoxic drug; five using therapeutic drug monitoring and two altering drug dosing to limit exposure. Overall, these prevention strategies ranged from $5,171 to $364,973 in total medical cost savings and $17 to $942 in total cost savings per patient-day. The in-hospital economic impact of D-AKI is substantial. Implementing nephrotoxin stewardship strategies to reduce D-AKI is associated with cost savings. Institutions should adopt strategic and efficient nephrotoxin stewardship programs to optimize patient care and reduce costs.

与急性肾损伤(AKI)的经济影响相关的信息很少,而与药物相关的急性肾损伤(D-AKI)的经济影响相关的信息则更少。我们的目标是全面总结 D-AKI 的经济负担,评估 D-AKI 与未发生 AKI 相比的成本,以及与肾毒性药物管理方法相关的成本节约。按照 PRISMA 指南,我们使用 PubMed 进行了文献检索,以确定从数据库建立之初到 2023 年 11 月期间的文章。主要结果包括 AKI 发生率、资源使用情况以及肾毒性药物管理计划/D-AKI 事件或无事件的成本。根据研究是否比较了D-AKI与未发生AKI的成本,或确定了与肾毒素管理方法相关的潜在成本节约,以预防D-AKI或D-AKI恶化,对主要研究结果进行了总结。所有成本均调整为 2023 美元。25 项研究符合纳入标准。八项研究比较了 D-AKI 与无 AKI 的成本。发生 D-AKI 的患者入院总费用从 47,696 美元到 173,569 美元不等。19 项研究实施了肾毒性药物管理,其中 12 项研究使用了肾毒性较低的药物替代品;5 项研究使用了治疗药物监测,2 项研究改变了药物剂量以限制药物暴露。总体而言,这些预防策略节省的医疗总成本从 5,171 美元到 364,973 美元不等,每个患者日节省的总成本从 17 美元到 942 美元不等。D-AKI 对院内经济的影响是巨大的。实施肾毒性药物管理策略以减少 D-AKI 与成本节约相关。医疗机构应采取战略性和高效的肾毒性药物管理计划,以优化患者护理并降低成本。
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引用次数: 0
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Clinical Pharmacology & Therapeutics
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