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Prediction of Cardiac ATTR Depletion by NI006 (ALXN2220) Using Mechanistic PK/PD Modeling. 利用机理 PK/PD 模型预测 NI006 (ALXN2220) 对心脏 ATTR 的消耗。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1002/cpt.3455
Aubin Michalon, Lionel Renaud, Matthias Machacek, Cédric Cortijo, Chandrasekhar Udata, Michele F Mercuri, Fabian Buller, Christoph Hock, Roger M Nitsch, Peter C Kahr, Jan Grimm

NI006 (aka ALXN2220) is a therapeutic antibody candidate in phase III clinical development for the depletion of amyloid transthyretin (ATTR) in patients with ATTR cardiomyopathy, an infiltrative cardiomyopathy leading to increased left ventricular wall thickness (LVWT). The mode-of-action consists in removal of disease-causing amyloid accumulations by activating phagocytic immune cells, a mechanism without precedent in cardiology. To select a safe and potentially efficacious dose range and treatment duration for a combined first-in-human and proof-of-concept clinical phase Ib study, we developed a mechanistic pharmacokinetic and pharmacodynamic (PK/PD) model that can predict NI006 exposure, its effects on cardiac amyloid load and on LWVT, which is a predictor of heart failure in this disease. The PK/PD model predictions supported 0.3 mg/kg monthly dosing as a safe starting dose and identified 10-60 mg/kg monthly as the potentially efficacious dose range with substantial and dose dependent cardiac amyloid burden reduction within 4 months for 60 mg/kg and 10 months for 10 mg/kg. These predictions were in good agreement with the observed primary results of the clinical phase Ib study where amyloid burden was measured by imaging. This novel translational PK/PD model provided important predictions to guide the design of the phase Ib study of NI006, indicating the value of this approach to integrate preclinical results into clinical trial design and increase translational success.

NI006(又名 ALXN2220)是一种处于 III 期临床开发阶段的候选治疗抗体,用于清除 ATTR 心肌病患者体内的淀粉样转甲状腺素(ATTR),ATTR 是一种导致左室壁厚度(LVWT)增加的浸润性心肌病。其作用模式是通过激活吞噬性免疫细胞来清除致病的淀粉样蛋白积聚,这种机制在心脏病学领域尚无先例。为了选择安全且具有潜在疗效的剂量范围和疗程,以进行首次人体试验和概念验证的 Ib 期临床研究,我们开发了一种机理药代动力学和药效动力学(PK/PD)模型,该模型可预测 NI006 的暴露量、其对心脏淀粉样蛋白负荷的影响以及对 LWVT 的影响,而 LWVT 是该疾病心力衰竭的预测指标。PK/PD模型预测支持将每月0.3毫克/千克的剂量作为安全的起始剂量,并确定每月10-60毫克/千克为潜在的有效剂量范围,60毫克/千克和10毫克/千克分别可在4个月和10个月内显著减少心脏淀粉样蛋白负荷,且减少量与剂量有关。这些预测与通过成像测量淀粉样蛋白负荷的 Ib 期临床研究的主要观察结果非常吻合。这种新颖的转化 PK/PD 模型为指导 NI006 Ib 期研究的设计提供了重要预测,表明了这种方法在将临床前结果整合到临床试验设计中并提高转化成功率方面的价值。
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引用次数: 0
Real-World Evidence in Regulatory Decision Making: Time for Evidence Integration 监管决策中的现实证据:证据整合的时机已到
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1002/cpt.3444
Rebecca A. Miksad
<p>Over the past decade, consideration of real-world evidence (RWE) in regulatory settings has come into sharper focus. The European Medicines Agency (EMA) and the United States (US) Food and Drug Administration (FDA) have chosen different paths to explore integrating RWE into decision-making processes.<span><sup>1, 2</sup></span> In this issue of Clinical Pharmacology & Therapeutics (CPT), Prilla <i>et al</i>.<span><sup>1</sup></span> evaluate the EMA's experience during the second stage (2021–2023) of an RWE pilot program that began in 2019.</p><p>The EMA employs a three-pronged approach to RWE generation: internal research, the DARWIN EU® network, and external pathways. Prilla <i>et al</i>.<span><sup>1</sup></span> demonstrate that research topics, typically requested during or in anticipation of regulatory procedures, are topical, practical, and support the scope of regulators and downstream decision-makers. This multifaceted RWE generation strategy using a flexible and comprehensive framework could serve as a model for other regulatory bodies.</p><p>The 61 RWE requests during the study time period offer several proof points for integrating RWE into evidence assessment. The RWE requests that were delivered offered timely insights from rapidly completed studies, enhanced understanding of clinical issues from diverse data sources, and informed plans for addressing unanswered questions. Nearly a quarter of the topics evaluated related to children, a group typically underrepresented in clinical trials even for conditions with a high pediatric burden.<span><sup>1, 3-5</sup></span> Almost half concerned rare diseases or orphan drugs, areas often lacking robust clinical trial data and detailed literature.<span><sup>6, 7</sup></span> The diversity of therapeutic areas covered, from anti-infectives to antineoplastic agents, underscores the potential broad applicability of RWE across disease areas. These RWE request pattern reflects global unmet regulatory needs that various policies have sought to address.</p><p>The prominence of requests related to age subgroups, pediatric investigational plans (PIP), and post-authorization study design suggests RWE's utility in compiling evidence for other historically underrepresented populations. In the United States, the FDA's Diversity Action Plan (DAP) requirement, updated in July 2024, presents opportunities for RWE to complement enrollment efforts at several junctures: creation of DAPs for registration enabling trials, evidentiary gaps at the time of regulatory procedures, and post-marketing requirements.<span><sup>8, 9</sup></span> A similar assessment in the United States of regulatory questions addressed with RWE, regardless of approval outcome, would be revealing.</p><p>The EMA's experience also outlines current limits of RWE in regulatory settings. Over a third of requests that completed feasibility assessment were unable to proceed, primarily due to lack of fit-for-purpose data.<span><sup>1</sup></s
在过去十年中,监管机构对真实世界证据(RWE)的考虑越来越受到关注。欧洲药品管理局(EMA)和美国食品和药物管理局(FDA)选择了不同的路径来探索将真实世界证据纳入决策过程。1, 2 在本期《临床药理学与amp; 治疗学》(CPT)杂志中,Prilla 等人1 评估了欧洲药品管理局在 2019 年开始的真实世界证据试点计划第二阶段(2021-2023 年)的经验。Prilla 等人1 证明,研究课题通常是在监管程序期间或预期监管程序期间提出的要求,它们具有主题性、实用性,并支持监管机构和下游决策者的工作范围。在研究期间提出的 61 项 RWE 请求为将 RWE 纳入证据评估提供了几个证明点。已提交的 RWE 申请及时提供了从快速完成的研究中获得的见解,加强了对来自不同数据源的临床问题的理解,并为解决未决问题提供了参考计划。近四分之一的评估主题与儿童有关,而这一群体在临床试验中的代表性通常较低,即使是儿科负担较重的疾病也是如此1, 3-5 近一半的主题涉及罕见病或孤儿药,这些领域通常缺乏可靠的临床试验数据和详尽的文献资料6, 7 从抗感染药物到抗肿瘤药物,所涉及的治疗领域多种多样,这突出表明了 RWE 在各疾病领域的潜在广泛适用性。这些 RWE 申请模式反映了全球未满足的监管需求,而这些需求正是各种政策所要解决的。与年龄亚组、儿科研究计划 (PIP) 和授权后研究设计相关的申请的突出表现表明,RWE 在为其他历史上代表性不足的人群收集证据方面具有实用性。在美国,FDA 于 2024 年 7 月更新的 "多样性行动计划"(DAP)要求为 RWE 提供了机会,使其能够在以下几个关键时刻补充注册工作:为注册授权试验创建 DAP、监管程序时的证据缺口以及上市后要求。在完成可行性评估的申请中,超过三分之一的申请无法继续进行,主要原因是缺乏符合目的的数据。1 EMA 不断扩大 RWE 能力,包括数据集的获取,以及 RWE 生成途径的多样化,这将拓宽和深化所解决的研究问题。有关课题可行性、时间安排和科学严谨性的持续透明度将有助于完善使用案例。RWE "供应 "与监管机构 "需求 "之间的最佳平衡仍不明确。欧洲药品管理局(EMA)的方法力求在效率和全面证据生成之间取得平衡。从流程的角度来看,RWE 额外信息的价值取决于其对决策点结果的影响。在临床试验数据仍是有效性黄金标准的监管环境中,RWE 可能会对决策的可信度产生最大影响,因此也会对额外研究(如有)的要求产生最大影响。因此,在监管环境之前或监管环境中花费时间和资源生成 RWE 的益处最好结合下游效应来考虑。将 RWE 纳入监管决策面临着常见的观察性研究挑战:(i) 适合目的的数据,这需要评估数据质量特征,如可靠性(完整性和准确性)和相关性;(ii) 减少偏倚和混杂的稳健方法。 10 在全球范围内实现 RWE 在监管决策中的潜力的关键步骤包括以下几点:(i) 统一数据标准和 RWE 方法,跨越监管、HTA 和支付方的背景和地域,以提高 RWE 研究结果的可比性和可移植性;(ii) 通过持续对话和知识共享,促进利益相关方(监管机构、HTA 和支付方、制药公司、医疗服务提供者、倡导者和患者)之间的密切合作,以找到一致点;(iii) 继续投资于强大的数据基础设施和先进的分析能力,包括人工智能和机器学习,以提高效率并解决最关键的知识差距(图 1)。CPT 将在计划于 2025 年 4 月出版的特刊《从基准到预算》中进一步探讨这种证据整合模式的转变。特刊 "从实验室到预算:简化药物开发和患者使用证据整合的全过程"。本期特刊将探讨当前药物开发、人口健康和经济评估交叉领域的机遇和挑战--RWE 在其中发挥着关键作用。当前和潜在的用例包括从药物发现和开发到药代动力学-药效学和临床前研究,从有效性和安全性的临床评估到监管审查,以及向医生、患者和支付治疗费用的付款人展示价值。Prilla 等人的研究既是概念的证明,也是对超越传统证据界限的行动号召。整合所有类型的证据,包括RWE、生成式人工智能和许多'omics',对于高效、个性化和以患者为中心的公平医疗保健至关重要。
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引用次数: 0
Longitudinal Analysis of Natural History Progression of Rare and Ultra-Rare Cerebellar Ataxias Using Item Response Theory 利用项目反应理论对罕见和超罕见小脑性共济失调的自然史进展进行纵向分析
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-15 DOI: 10.1002/cpt.3466
Alzahra Hamdan, Niels Hendrickx, Andrew C. Hooker, Xiaomei Chen, Emmanuelle Comets, Andreas Traschütz, Rebecca Schüle, ARCA Study Group, EVIDENCE-RND Consortium, France Mentré, Matthis Synofzik, Mats O. Karlsson

Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra-rare genetic diseases. While disease-modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real-world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix–Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75–90% less with 5 years vs. 2 years), and larger drug effects (~ 70–80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well-controlled type I error, compared to total score models or end-of-treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra-rare genetic ataxias.

退行性小脑性共济失调是一组异质性的罕见和超罕见遗传疾病。虽然针对许多小脑性共济失调症的疾病改变疗法已箭在弦上,但仍缺乏可靠的试验设计和分析方法。为了更好地为试验设计提供信息,我们应用项目反应理论(IRT)建模来评估几种共济失调的自然史进展,并使用广泛使用的共济失调评估和评级量表(SARA)进行评估。我们利用大型常染色体隐性小脑共济失调(ARCA)登记处的实际数据建立了一个纵向 IRT 模型。该模型评估了整个队列以及 10 种最常见的 ARCA 基因型的疾病进展情况。对常染色体隐性痉挛性共济失调沙勒瓦-萨盖奈(ARSACS)和聚合酶γ(POLG)共济失调的模拟试验进行了样本量计算,展示了多种设计和分析方案。纵向 IRT 模型能够描述作为共济失调发病时间函数的 SARA 潜在变量在整个 ARCA 队列和常见基因型中的变化。不同基因型的典型进展率各不相同,POLG 的进展率相对较高(SARA = 20 时约为 0.98 SARA 点/年),而 COQ8A 共济失调的进展率则非常低(SARA = 20 时约为 0.003 SARA 点/年)。如果病情进展较快、试验时间较长(5 年与 2 年相比减少 75-90%)、药物作用较大(100% 抑制与 50% 抑制相比减少 70-80%),则需要较小的试验规模。在已开发的 IRT 模型下进行模拟,与总分模型或治疗末期分析相比,纵向 IRT 模型的功率最高,I 型误差控制得很好。已建立的纵向 IRT 框架可有效利用自然病史数据,最终促进罕见和超罕见遗传性共济失调治疗试验的设计和分析。
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引用次数: 0
Drug-Drug Interaction Between Dihydroartemisinin-Piperaquine and Sulfadoxine-Pyrimethamine During Malaria Chemoprevention in Pregnant Women. 孕妇在疟疾化学预防过程中双氢青蒿素-哌喹与磺胺乙胺嘧啶之间的药物相互作用
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-14 DOI: 10.1002/cpt.3471
Norah Mwebaza, Michelle E Roh, Yourong Z Geng, Leonard Opio, Bishop Opira, Florence Marzan, Moses W Mwima, Timothy Ssemukuye, Kevin Guo, David Gingrich, Nikoletta Fotaki, Abel Kakuru, Jimmy Kizza, Miriam Aguti, Harriet Adrama, Moses Kamya, Grant Dorsey, Philip J Rosenthal, Francesca T Aweeka, Liusheng Huang

Co-administration of dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria in pregnancy (IPTp) may be superior in preventing adverse birth outcomes compared with either therapy alone, but potential drug-drug interactions require investigation. We conducted intensive and sparse pharmacokinetic (PK) studies in a subset of Ugandan women participating in a randomized controlled trial of monthly IPTp with SP vs. DP vs. DP + SP. Intensive PK sampling was performed from day 0 to 23 after dosing at 28 weeks gestation in 87 participants across treatment arms. Sparse sampling was performed on day 28 (trough) after dosing at 20 and 28 gestational weeks in additional 196 participants receiving SP vs. DP + SP. Intensive PK analysis demonstrated that compared with SP alone, co-administration of DP + SP was associated with lower maximal concentrations, the area under the concentration-time curves (AUC), and day 23 concentrations of sulfadoxine (25%, 25%, and 27%) and pyrimethamine (26%, 34%, and 32%) (P < 0.05 for all comparisons). Sparse PK results demonstrated participants co-administered DP + SP had lower trough concentrations after dosing at 20 and 28 gestational weeks for sulfadoxine (6%, P = 0.68 and 31%, P = 0.023, respectively) and pyrimethamine (18%, P = 0.032 and 33%, P < 0.001, respectively) compared with SP alone. Co-administration of DP + SP was associated with a 19% reduction in piperaquine AUC (P = 0.046), but no significant difference in other PK parameters compared with DP alone. In summary, co-administration of DP + SP was associated with significantly reduced SP exposure, with a greater magnitude during the third vs. second trimester. The clinical consequences of this interaction are yet unknown.

在妊娠期疟疾间歇预防性治疗(IPTp)中联合使用双氢青蒿素哌喹(DP)和磺胺乙胺嘧啶(SP)可能比单独使用其中一种疗法更能预防不良分娩结局,但需要对潜在的药物相互作用进行调查。我们对参加每月使用 SP 与 DP 与 DP + SP 的间歇性预防治疗随机对照试验的部分乌干达妇女进行了密集和稀疏的药代动力学(PK)研究。在妊娠 28 周用药后的第 0 天到第 23 天,对 87 名不同治疗组的参与者进行了强化 PK 采样。在妊娠20周和28周用药后的第28天(低谷),对另外196名接受SP与DP+SP治疗的参与者进行了稀释取样。强化 PK 分析表明,与单独服用 SP 相比,联合服用 DP + SP 与磺胺多辛(25%、25% 和 27%)和乙胺嘧啶(26%、34% 和 32%)的最大浓度、浓度-时间曲线下面积(AUC)和第 23 天浓度较低(P<0.05)有关。
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引用次数: 0
The Impact of QT-Prolonging Medications and Drug-Drug Interactions on QTc Interval Prolongation in Hospitalized Patients: A Case-Crossover Study. QT 延长药物和药物间相互作用对住院患者 QTc 间期延长的影响:病例交叉研究
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-09 DOI: 10.1002/cpt.3469
Hsiu-Ting Chien, Fang-Ju Lin, Jyh-Ming Jimmy Juang, Shu-Wen Lin

Researchers have studied potential corrected QT interval (QTc) prolongation from drug-drug interactions (DDIs), raising unresolved questions about their real-world impact. This retrospective case-crossover study investigated the effects of QT-prolonging drugs and DDIs on QTc prolongation in hospitalized patients aged 45 years and above. The cohort comprised patients who had multiple hospitalizations and developed QTc prolongation (QTc > 500 ms or an increase of >60 ms from baseline) at least 24 hours after admission between 2011 and 2019. Conditional logistic regression compared drug exposure between hospitalizations with QTc prolongation (case window) and those without (reference window). Among 2,276 patients (mean age 71; 43.8% female), the use of QT-prolonging drugs significantly increased the risk of QTc prolongation (odds ratio: 2.42 (95% confidence interval: 1.95-3.02)). The risk was higher with drugs of "known risks" (OR: 3.78 (2.91-4.90)) and "conditional risk" (OR: 2.08 (1.65-2.62)). DDIs, particularly involving multiple "known risk" drugs (OR: 7.86 (4.96-12.45)), strong cytochrome P450 enzyme inhibitors (OR: 5.57 (2.75-11.30)), or the concurrent use of ≥4 QT-prolonging drugs with any risk (OR: 5.28 (3.96-7.03)) substantially increased the risk. Cautious prescribing for patients with multiple risk factors is important to minimize the likelihood of QTc prolongation. However, when considering enhanced monitoring or drug choices, it is crucial to carefully evaluate the overall risk of QT prolongation against the benefits of treatment to ensure optimal patient care.

研究人员对药物间相互作用(DDI)可能导致的校正 QT 间期(QTc)延长进行了研究,但对其在现实世界中的影响提出了一些尚未解决的问题。这项回顾性病例交叉研究调查了 QT 延长药物和 DDI 对 45 岁及以上住院患者 QTc 延长的影响。研究对象包括2011年至2019年期间多次住院并在入院后至少24小时内出现QTc延长(QTc>500毫秒或比基线增加>60毫秒)的患者。条件逻辑回归比较了有 QTc 延长(病例窗)和无 QTc 延长(参考窗)的住院患者之间的药物暴露情况。在2276名患者(平均年龄71岁;43.8%为女性)中,使用QT延长药物会显著增加QTc延长的风险(几率比:2.42(95%置信区间:1.95-3.02))。使用 "已知风险 "药物(OR:3.78(2.91-4.90))和 "有条件风险 "药物(OR:2.08(1.65-2.62))的风险更高。DDIs,尤其是涉及多种 "已知风险 "药物(OR:7.86(4.96-12.45))、强细胞色素 P450 酶抑制剂(OR:5.57(2.75-11.30))或同时使用≥4 种具有任何风险的 QT 延长药物(OR:5.28(3.96-7.03))会大大增加风险。对具有多种风险因素的患者谨慎用药,对于最大限度地降低 QTc 延长的可能性非常重要。但是,在考虑加强监测或选择药物时,必须仔细评估 QT 延长的总体风险与治疗的益处,以确保为患者提供最佳护理。
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引用次数: 0
Selected Acute Safety Events Following the Use of Nirmatrelvir/Ritonavir or Molnupiravir for COVID-19: A Nationwide Cohort Study in South Korea. COVID-19使用Nirmatrelvir/Ritonavir或Molnupiravir后的部分急性安全事件:韩国全国队列研究。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-08 DOI: 10.1002/cpt.3461
Ju Hwan Kim, Ahhyung Choi, Gihwan Bae, Eun-Jeong Joo, Min Joo Choi, Kyungmin Huh, Hyungmin Lee, Jungyeon Kim, Dong-Hwi Kim, Min-Gyu Yoo, Il Uk Jo, Poong Hoon Lee, Geun Woo Lee, Hee Sun Jung, Jaehun Jung, Ju-Young Shin

There had been concerns about the acute complications during or shortly after coronavirus disease 2019 (COVID-19) treatment with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL). This study aimed to compare the risks of selected acute safety events in patients treated with or without NMVr or MOL using the COVID-19 oral treatment safety assessment data, constructed through the linkage of nationwide databases: National COVID-19 registry, Real-time Prescription Surveillance, and National Health Insurance data. We identified all adults diagnosed with COVID-19 between January and November 2022, and then constructed two cohorts by matching up to four patients without antiviral treatment records to NMVr or MOL users using propensity score matching. Outcomes of interest were incident-selected cardiac (i.e., atrial fibrillation, other arrhythmia, bradycardia), neurological (i.e., seizure, neuropathy, encephalomyelitis), and miscellaneous (i.e., acute pancreatitis, acute liver injury, dysgeusia) events. A total of 739,935 NMVr users were matched with 2,951,690 comparators and 150,431 MOL users with 759,521 comparators. NMVr users were at lower risk for developing selected cardiac events (hazard ratio 0.74 [95% CI 0.65-0.87] for atrial fibrillation, 0.81 [0.65-0.99] for other arrhythmia, and 0.82 [0.70-0.96] for bradycardia) and dysgeusia (0.58 [0.45-0.74]). For MOL users, the risk was lower for atrial fibrillation (0.72 [0.53-0.96]) and dysgeusia (0.34 [0.18-0.65]). Overall, there were no increased risks of acute complications during and shortly after treatment with oral COVID-19 antivirals. Rather, the findings underscore their effectiveness in attenuating the risk of potential acute sequelae of COVID-19.

在使用尼马瑞韦/利托那韦(NMVr)和莫鲁吡拉韦(MOL)治疗2019年冠状病毒病(COVID-19)期间或治疗后不久,急性并发症一直备受关注。本研究旨在利用通过全国性数据库链接构建的 COVID-19 口服治疗安全性评估数据,比较接受或不接受 NMVr 或 MOL 治疗的患者发生特定急性安全事件的风险:全国 COVID-19 登记、实时处方监控和国民健康保险数据。我们确定了 2022 年 1 月至 11 月期间确诊为 COVID-19 的所有成年人,然后通过倾向得分匹配法将多达四名无抗病毒治疗记录的患者与 NMVr 或 MOL 使用者进行匹配,构建了两个队列。研究结果为事件选择的心脏(即心房颤动、其他心律失常、心动过缓)、神经(即癫痫发作、神经病变、脑脊髓炎)和其他(即急性胰腺炎、急性肝损伤、消化不良)事件。共有 739,935 名 NMVr 使用者与 2,951,690 名比较者进行了配对,150,431 名 MOL 使用者与 759,521 名比较者进行了配对。NMVr 用户发生特定心脏事件的风险较低(心房颤动的危险比为 0.74 [95% CI 0.65-0.87],其他心律失常的危险比为 0.81 [0.65-0.99],心动过缓的危险比为 0.82 [0.70-0.96]),发生呼吸困难的风险也较低(0.58 [0.45-0.74])。MOL使用者的心房颤动(0.72 [0.53-0.96])和心动过速(0.34 [0.18-0.65])风险较低。总体而言,在口服 COVID-19 抗病毒药物治疗期间和治疗后不久,急性并发症的风险并没有增加。相反,研究结果强调了口服 COVID-19 抗病毒药物在降低潜在急性后遗症风险方面的有效性。
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引用次数: 0
Pathway-Based Similarity Measurement to Quantify Transcriptomics Similarity Between Human Tissues and Preclinical Models. 基于通路的相似性测量法量化人体组织与临床前模型之间的转录组学相似性
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-08 DOI: 10.1002/cpt.3465
Paarth Parekh, Jason Sherfey, Begum Alaybeyoglu, Murat Cirit

Accurate clinical translation of preclinical research remains challenging, primarily due to species-specific differences and disease and patient heterogeneity. An important recent advancement has been development of microphysiological systems that consist of multiple human cell types that recapitulate key characteristics of their respective human systems, allowing essential physiologic processes to be accurately assessed during drug development. However, an unmet need remains regarding a quantitative method to evaluate the similarity between diverse sample types for various contexts of use (CoU)-specific pathways. To address this gap, this study describes the development of pathway-based similarity measurement (PBSM), which leverages RNA-seq data and pathway-based information to assess the human relevance of preclinical models for specific CoU. PBSM offers a quantitative method to compare the transcriptomic similarity of preclinical models to human tissues, shown here as proof of concept for liver and cardiac tissues, enabling improved model selection and validation. Thus, PBSM can successfully support CoU selection for preclinical models, assess the impact of different gene sets on similarity calculations, and differentiate among various in vitro and in vivo models. PBSM has the potential to reduce the translational gap in drug development by allowing quantitative evaluation of the similarity of preclinical models to human tissues, facilitating model selection, and improving understanding of context-specific applications. PBSM can serve as a foundation for enhancing the physiological relevance of in vitro models and supporting the development of more effective therapeutic interventions.

临床前研究的准确临床转化仍然具有挑战性,这主要是由于物种特异性差异以及疾病和患者的异质性。最近的一项重要进展是开发了微观生理系统,该系统由多种人类细胞类型组成,可再现各自人类系统的关键特征,从而在药物开发过程中准确评估基本生理过程。然而,对于评估不同样本类型在不同使用环境(CoU)特异性通路中的相似性的定量方法,仍有未满足的需求。为了填补这一空白,本研究介绍了基于通路的相似性测量(PBSM)的开发情况,它利用 RNA-seq 数据和基于通路的信息来评估临床前模型与特定 CoU 的人体相关性。PBSM 提供了一种定量方法来比较临床前模型与人体组织的转录组相似性,这里显示的是肝脏和心脏组织的概念验证,从而改进了模型的选择和验证。因此,PBSM 可以成功支持临床前模型的 CoU 选择,评估不同基因组对相似性计算的影响,并区分各种体外和体内模型。PBSM 可以定量评估临床前模型与人体组织的相似性,促进模型选择,并提高对特定环境应用的理解,从而有可能缩小药物开发的转化差距。PBSM 可作为增强体外模型生理相关性的基础,并支持开发更有效的治疗干预措施。
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引用次数: 0
Value of Pharmacogenetic Testing Assessed with Real-World Drug Utilization and Genotype Data. 利用真实世界的药物使用情况和基因型数据评估药物基因检测的价值。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-04 DOI: 10.1002/cpt.3458
Kaisa Litonius, Noora Kulla, Petra Falkenbach, Kati Kristiansson, E Katriina Tarkiainen, Liisa Ukkola-Vuoti, Kristiina Cajanus, Mari Korhonen, Sofia Khan, Johanna Sistonen, Arto Orpana, Mats Lindstedt, Tommi Nyrönen, Markus Perola, Miia Turpeinen, Ville Kytö, Aleksi Tornio, Mikko Niemi

Implementation of pharmacogenetic testing in clinical care has been slow and with few exceptions is hindered by the lack of real-world evidence on how to best target testing. In this retrospective register-based study, we analyzed a nationwide cohort of 1,425,000 patients discharged from internal medicine or surgical wards and a cohort of 2,178 university hospital patients for purchases and prescriptions of pharmacogenetically actionable drugs. Pharmacogenetic variants were obtained from whole genome genotype data for a subset (n = 930) of the university hospital patients. We investigated factors associated with receiving pharmacogenetically actionable drugs and developed a literature-based cost-benefit model for pre-emptive pharmacogenetic panel testing. In a 2-year follow-up, 60.4% of the patients in the nationwide cohort purchased at least one pharmacogenetically actionable drug, most commonly ibuprofen (25.0%) and codeine (19.4%). Of the genotyped subset, 98.8% carried at least one actionable pharmacogenetic genotype and 23.3% had at least one actionable gene-drug pair. Patients suffering from musculoskeletal or cardiovascular diseases were more prone to receive pharmacogenetically actionable drugs during inpatient episode. The cost-benefit model included frequently dispensed drugs in the university hospital cohort, comprising ondansetron (19.4%), simvastatin (7.4%), clopidogrel (5.0%), warfarin (5.1%), (es)citalopram (5.3%), and azathioprine (0.5%). For untargeted pre-emptive pharmacogenetic testing of all university hospital patients, the model indicated saving €17.49 in direct healthcare system costs per patient in 2 years without accounting for the cost of the test itself. Therefore, it might be reasonable to target pre-emptive pharmacogenetic testing to patient groups most likely to receive pharmacogenetically actionable drugs.

药物基因检测在临床治疗中的应用一直进展缓慢,除少数例外情况外,还因缺乏关于如何最有针对性地进行检测的实际证据而受到阻碍。在这项以登记为基础的回顾性研究中,我们分析了全国范围内 142.5 万名内科或外科病房出院患者的队列以及 2178 名大学医院患者的队列,了解他们购买和开具药物遗传学可操作性药物处方的情况。药物基因变异是从大学医院患者子集(n = 930)的全基因组基因型数据中获得的。我们调查了与接受药物遗传学可操作性药物相关的因素,并开发了一个基于文献的先期药物遗传学面板检测成本效益模型。在为期 2 年的随访中,全国范围内有 60.4% 的患者至少购买了一种药物基因作用药物,其中最常见的是布洛芬(25.0%)和可待因(19.4%)。在基因分型子群中,98.8%的人携带至少一种可操作的药物基因型,23.3%的人拥有至少一对可操作的基因-药物配对。患有肌肉骨骼或心血管疾病的患者在住院期间更容易接受可作用的药物。成本效益模型包括大学医院队列中的常用药物,包括昂丹司琼(19.4%)、辛伐他汀(7.4%)、氯吡格雷(5.0%)、华法林(5.1%)、(ES)西酞普兰(5.3%)和硫唑嘌呤(0.5%)。如果对所有大学医院的患者进行无针对性的先期药物基因检测,模型显示,在不考虑检测成本的情况下,2 年内每位患者可节省 17.49 欧元的直接医疗系统成本。因此,针对最有可能接受药物遗传学可操作性药物的患者群体进行先期药物遗传学检测可能是合理的。
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引用次数: 0
Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Studies Related to Vincristine-Induced Peripheral Neuropathy in Chinese Pediatric ALL Patients. 中国小儿 ALL 患者长春新碱诱发周围神经病变的药代动力学、药效学和药物遗传学研究
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-04 DOI: 10.1002/cpt.3462
Yawen Yuan, Wenting Hu, Changcheng Chen, Ruen Yao, Shunguo Zhang, Xiao Zhu, Bulong Xu, Zhonghui Huang, Shengyuan Zhang, Xuexian Wang, Mei Zheng, Xiaohui Huang, Joseph F Standing

Vincristine (VCR) can cause vincristine-induced peripheral neuropathy (VIPN) during the treatment of acute lymphoblastic leukemia (ALL) and the mechanisms are complicated. The aim of this study was to investigate the influencing factors on the population pharmacokinetics (PopPK) and pharmacodynamics (PD) related to VIPN, including clearance routes, drug-drug interactions (DDI), and genetic characteristics. Pediatric patients being treated for ALL were recruited to PK study where VCR and its metabolite (M1) were measured using a novel assay. The incidence of VIPN was also recorded. DNA sequencing of relevant PK and PD genes was performed. PopPK and PK/PD models were developed, pharmacogenetic and DDI analyses were conducted. In total, 79 children were recruited. The results showed that allometric scaling, ABCB1-rs1128503 genotype, and posaconazole (POS) significantly improved the PopPK model fit. VIPN was significantly correlated with the exposure of VCR. Co-administration with POS shifted the effect curve for VIPN to the left, indicating increased VIPN risk at the same exposure levels. No significant effects on VIPN were observed for CYP3A5 (rs776746), CYP3A4 (rs2242480), CEP72 (rs924607), or various ABCB1 variants (rs1128503, rs2032582, rs1045642, rs4728709, rs4148737, and rs10276036), nor with the co-administration of fluconazole or dasatinib. In summary, co-administration of POS increased VCR exposure by 0.4-fold and raised the risk of VIPN, with an occurrence probability generally exceeding 0.7. Therapeutic drug monitoring of VCR in clinical practice may be necessary to enable appropriate dose adjustments and individualized treatment.

长春新碱(VCR)在急性淋巴细胞白血病(ALL)的治疗过程中可引起长春新碱诱导的周围神经病变(VIPN),其机制十分复杂。本研究旨在调查与VIPN相关的群体药代动力学(PopPK)和药效学(PD)的影响因素,包括清除途径、药物间相互作用(DDI)和遗传特征。PK研究招募了接受ALL治疗的儿童患者,使用一种新型检测方法测量VCR及其代谢物(M1)。同时还记录了VIPN的发生率。对相关的 PK 和 PD 基因进行了 DNA 测序。建立了 PopPK 和 PK/PD 模型,并进行了药物遗传学和 DDI 分析。共招募了 79 名儿童。结果显示,异速缩放、ABCB1-rs1128503 基因型和泊沙康唑(POS)能显著提高 PopPK 模型的拟合度。VIPN 与 VCR 暴露有明显的相关性。与 POS 同时给药会使 VIPN 的效应曲线向左移动,这表明在相同的暴露水平下,VIPN 的风险会增加。CYP3A5(rs776746)、CYP3A4(rs2242480)、CEP72(rs924607)或各种ABCB1变体(rs1128503、rs2032582、rs1045642、rs4728709、rs4148737和rs10276036)对VIPN没有明显影响,同时服用氟康唑或达沙替尼也没有明显影响。总之,合用 POS 会使 VCR 暴露增加 0.4 倍,并增加发生 VIPN 的风险,发生概率一般超过 0.7。在临床实践中可能有必要对 VCR 进行治疗药物监测,以便进行适当的剂量调整和个体化治疗。
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引用次数: 0
Pharmacokinetic, Safety, and Pharmacodynamic Profiles of Saroglitazar Magnesium in Cholestatic Cirrhosis With Hepatic Impairment and Participants With Renal Impairment. 肝功能受损的胆汁淤积性肝硬化患者和肾功能受损者服用沙格列扎镁的药代动力学、安全性和药效学概况
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-10-02 DOI: 10.1002/cpt.3450
Raj Vuppalanchi, Mary M Cruz, Taufik Momin, Farheen Shaikh, Kimberly Swint, Harilal Patel, Deven Parmar

Saroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns.

沙格列扎镁是一种 PPAR α/γ 双激动剂,目前正处于治疗原发性胆汁性胆管炎 (PBC) 的 III 期临床阶段,研究人员评估了它在不同肝功能损害程度 (HI) 的胆汁淤积性肝病 (CLD) 患者和严重肾功能损害 (RI) 患者中的药代动力学 (PK) 特征、安全性和药效学。共进行了三项 PK 研究,将沙格列扎与健康对照组进行比较:研究 1 对 12 名轻度或中度 HI 的 PBC 肝硬化患者进行了为期 4 周、每天口服 1 或 2 毫克的研究;研究 2 评估了 8 名非肝硬化 CLD 患者的单剂量 PK(2 或 4 毫克);研究 3 评估了 8 名严重 RI 患者的单剂量 PK(2 毫克)。第 1 天,与正常人相比,轻度 HI 患者的沙格列扎尔暴露量增加了 14.6-42%,但到第 28 天,暴露量水平相似,表明没有蓄积。在中度 HI 中,第 1 天和第 28 天的暴露量显著增加了 50.4-85%,尽管半衰期相似,但清除率降低了 34-46%。中度 HI 组的暴露量比非肝硬化组高 59%。沙格列扎尔(1 毫克和 2 毫克)可在 4 周后将基线 ALP 异常者的碱性磷酸酶 (ALP) 水平降低 17-40%。非肝硬化CLD(2毫克和4毫克)和严重RI(2毫克)患者的单剂量PK值与匹配对照组相当,没有明显的安全性问题。总体而言,沙格列扎尔(1 毫克和 2 毫克)在胆汁淤积性肝硬化轻度 HI 和重度 RI 患者中安全且耐受性良好,没有重大 PK 变化。中度 HI 会增加暴露量并降低清除率,但不存在任何安全问题。
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引用次数: 0
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