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IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-20 DOI: 10.1002/cpt.3376
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引用次数: 0
Getting the Dosage Right: A Vital Role for Clinical Pharmacology in the Era of Precision Medicine 正确掌握剂量:精准医学时代临床药理学的重要作用》。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-20 DOI: 10.1002/cpt.3375
Iris K. Minichmayr, Mohamad Shebley, Piet H. van der Graaf, Karthik Venkatakrishnan
<p>Right dosage—administering the right dose at the right time in the optimal dosing interval using the appropriate application route and administration method—is central to the role of clinical pharmacology throughout the development and clinical use of therapeutics. It is critically important in all therapeutic areas to maximize patient benefit and minimize undesirable adverse effects. Getting the dosage right extends beyond population-level dosing to meet a certain efficacy or toxicity threshold in a defined patient group or subgroup of interest, such as patients with a specific indication or certain degree of organ impairment. As the “one-size-fits-all” concept often fails to optimize the benefit–risk ratio for all patients in clinical practice, various precision dosing strategies, acknowledging between-patient variability in exposure and/or response, have been evolving to tailor dosage regimens and increase the chances of treatment success for <i>individual</i> patients. Just as a sculptor meticulously chisels away at a block of marble to reveal a masterpiece, dose finding in drug development and precision dosing involves carefully tailoring dosage regimens to the disease of concern and the unique characteristics of patients (<b>Figure</b> 1). This special-themed issue of <i>Clinical Pharmacology & Therapeutics</i> illuminates various aspects, advancements, and future perspectives in getting the dosage right in drug development, regulatory approval, and clinical practice.</p><p>Dose selection and optimization have been particularly prominent topics in oncology in recent years, not least since the launch of Project Optimus by the US Food and Drug Administration.<span><sup>1</sup></span> This initiative aims to reform dose selection to maximize not only the efficacy of a drug, but also its safety and tolerability. In this issue, two papers provide comprehensive viewpoints on the topic of oncology dosage optimization from the regulatory and pharmaceutical industry sectors, respectively. In their State-of-the-Art review, Rahman <i>et al</i>. offer a regulatory perspective highlighting the foundational importance of timely dosage optimization and the consequences of not doing so.<span><sup>2</sup></span> The authors discuss the topic in the context of the realities of rapid development programs, rare and pediatric cancers, and combination development, outlining the value of tools in translational and precision medicine, and model-informed drug development for achieving the desired objectives. A White Paper by the Oncology Dose Optimization Working Group, commissioned by the International Consortium for Innovation and Quality in Pharmaceutical Development, highlights the impact of Project Optimus on oncology dose optimization, together with common issues and potential solutions, post-marketing requirements and commitments, as well as insights from a survey on current industry practices for oncology dose selection.<span><sup>3</sup></span> The
18 虽然该领域的进展为提高精准给药带来了希望,但要将其临床应用到医疗保健生态系统中,还需要在临床实践环境中推广此类研究,并推进相关的监管框架和政策制定,以弥合从实验室到床边的差距,充分实现这些创新的前景。虚拟双胞胎研究还揭示了与药物代谢和处置相关的 500 个酶和转运体靶点的 mRNA 表达,这只是挑战 "一刀切 "方法之外的 "一靶点万能 "理念的一个例子。19 用于剂量优化的临床定量药理学方法正以惊人的创新速度向前发展,生物学驱动的疾病模型的进步和数据科学的创新使系统医学框架得以注入。定量系统药理学(QSP)模型考虑了先天性免疫反应和适应性免疫反应等生物系统的详细组成部分,因此具有很高的机理可解释性。本期 CPT 内容包括通过预测对抗病毒疗法的反应来帮助在紧急健康危机期间进行有模型指导的决策的 QSP 框架20,以及一个案例研究,该案例研究说明了如何利用 QSP 模型进行有模型指导的精确用药21。机器学习方法也已进入用药研究领域,例如,在开发有模型指导的精确用药算法以支持更安全、更有效的处方22。23 剂量优化方面的创新对于在新适应症和患者群体监管审批的效益/风险评估背景下生成证据至关重要。Al-Khouja 等人在文章中从监管角度阐述了 FDA 批准霉酚酸酯(mycophenolate mofetil)用于预防小儿心脏或肝脏移植患者的器官排斥反应,他们概述了支持定义适当剂量范围的证据,这些证据利用了从成人环境中进行外推的原则,以及整合了特定适应症和人群中所有可用知识的证据整体方法。针对儿童群体的药物开发需要全面评估体型/体重和年龄对全身暴露的影响,以确定适当的剂量。25 一项回顾性数据库审查对当前的剂量策略,特别是体型对剂量结果的影响进行了描述,并与成人剂量策略进行了比较。药物研发成功并获得批准后,在临床实践中采用适当的给药剂量是关键,但也并非无足轻重,有报告指出真实世界临床结果的价值27 以及批准后在特定人群中持续优化剂量,即使是万古霉素和他莫昔芬等已在临床实践中使用数十年的老药也是如此28,29。然而,正如 Abdel-Rahman 等人和 Morales Junior 等人在他们的行动呼吁中所讨论的那样,TDM 在许多药物中的作用还存在争议,在医疗保健生态系统中将其转化为临床实践还有许多机会。例如,一个 CDS 应用程序有可能加强镰状细胞贫血患儿的羟基脲治疗,尤其是在没有临床药理学专业知识的地方34。现在有机会扩展此类应用程序,不仅纳入 PK 数据,还纳入相关的药效学/安全性生物标志物数据,并使用机理性联合群体 PK-PD 模型进行整合35。目前还在努力简化采样和居家 PK 测量,以便调整用药剂量,如另一项研究所示,该研究评估了以患者为中心的低容量毛细管液体和干血采样设备,适用于各种大分子和小分子药物。
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引用次数: 0
Model-Informed Approaches to Optimizing Therapeutics in the African Patient Populations 在非洲患者群体中优化治疗方法的模型启发法。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-20 DOI: 10.1002/cpt.3425
Mwila Mulubwa, Kelly Chibale
<p>Pharmacokinetics variability arises from individual differences in how drugs are absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetic variations can be influenced by several intrinsic and extrinsic factors, including genetic polymorphisms, weight, sex, age, disease state, or polypharmacy.<span><sup>1</sup></span> Genetic factors such as polymorphisms in drug metabolizing enzymes can account for 20 to 95 percent patient variability in response to individual pharmacotherapy.<span><sup>1</sup></span></p><p>Understanding the genetic diversity in genes encoding for drug-metabolizing enzymes is essential in facilitating the development of more effective therapeutics tailored to diverse populations. Africa exhibits higher genetic diversity than other populations worldwide, a characteristic that extends to variability within genes encoding the cytochrome P450 enzyme system and drug transporter proteins.<span><sup>2</sup></span> It is noteworthy that genetic variability in African populations is not representative of that in the African American population and therefore cannot be assumed to be similar. Variations in gene sequence ultimately translate into decreased, normal, increased, or no enzyme function. This gives rise to metabolic phenotypes such as poor metabolizers, normal metabolizers, and fast metabolizers, which are associated with adverse drug reactions, suboptimal treatment efficacy, and poor treatment outcomes, respectively. This genetic variability has contributed to the high incidences of adverse drug reactions and poor therapeutic outcomes, especially in tuberculosis (TB) and human immunodeficiency virus (HIV) cases reported in Africa.<span><sup>2</sup></span> Hence, variations in pharmacokinetics pose challenges and create disparities in treatment outcomes among the genetically diverse African populations.</p><p>These challenges are compounded by lack of sufficiently powered clinical pharmacokinetics or pharmacogenetics studies to accurately quantify the influence of the prevalent pharmacogenetic variants on drug exposure in most African populations.<span><sup>3</sup></span> In addition, despite Africa accounting for around 15% of the global population, it remains understudied and largely absent from biomedical research. Therefore, it is indispensable to adopt model-informed strategies to address disparities in therapeutic outcomes among African patient populations. These approaches involve the application of data-driven models to guide decision-making and optimize therapeutic interventions for African patient populations. In the absence of African-derived biobanks, this requires the building or refining of existing physiologically based pharmacokinetic (PBPK) models that factor in African genetic variants predicted from artificial intelligence (AI) as illustrated in <b>Figure</b> 1. Here, we propose <i>in vitro</i> and <i>in silico</i> methods that may help explain pharmacokinetic variability and inform dose r
在一大批接受一线抗结核药物(异烟肼、利福平、吡嗪酰胺和乙胺丁醇)治疗的非洲患者中显示,Mtb细菌负荷从平均基线6 log10 CFU/mL持续到治疗12周后的平均2 log10 CFU/mL。因此,Mtb 介导的药物代谢可能会对结核病或其他合并症的疗效和治疗结果产生潜在影响,而结核病或其他合并症的药物治疗可能易受 Mtb 介导的代谢影响。非线性混合效应建模方法允许将 Mtb 介导的代谢或遗传因素作为协变量纳入这些数学模型并进行建模,从而能够探索复杂的药代动力学方案。通过利用 PBPK 模型预测的药代动力学数据,NLME 模型可以描述药物暴露的变异性,并确定遗传因素、人口统计学和结核病等疾病状态等因素是影响治疗结果的重要协变量。基于 NLME 模型的仿真技术可以对不同的给药策略、治疗持续时间和联合疗法进行硅学探索,10 为特定非洲患者群体的最佳治疗方案设计提供有价值的见解。以模型为依据的方法为优化非洲患者群体的治疗方案提供了一条前景广阔的途径。通过使用非洲肝脏亚细胞组分或 AI 预测的非洲流行基因变异(药物代谢酶)建立 PBPK 模型,并将 Mtb 介导的药物代谢纳入 PBPK 模型,我们可以预测并捕捉药代动力学变异。PBPK模拟药代动力学特征的NLME建模增强了对药物基因变异性的理解,从而能够开发出更有针对性和更精确的治疗方案,最大限度地降低药物不良反应的风险,优化非洲人群的治疗效果。K.C.是以非洲为中心的药物发现和开发领域的Neville Isdell讲席教授,感谢Neville Isdell对该讲席教授的慷慨资助。
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引用次数: 0
Neuron-Derived Extracellular Vesicles miRNA Profiles Identify Children Who Experience Adverse Events after Ketamine Administration for Procedural Sedation. 神经元衍生细胞外小泡 miRNA 图谱可识别因手术镇静而使用氯胺酮后出现不良反应的儿童。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-20 DOI: 10.1002/cpt.3420
Marianna Lucafò, Carlotta Bidoli, Martina Franzin, Erez Eitan, Sara Rau, Alessandro Amaddeo, Alice Fachin, Adamo Pio d'Adamo, Giuliana Decorti, Gabriele Stocco, Egidio Barbi, Giorgio Cozzi

Ketamine provides the highest safety profile among sedatives for procedural sedation and analgesia in the pediatric emergency setting. However, it can cause vomiting and recovery agitation. No studies have examined epigenetic factors, such as microRNAs, for predicting the occurrence of these adverse events. Neuronal-derived extracellular vesicle microRNA profiles were studied to predict the occurrence of ketamine-induced vomiting and recovery agitation in children. For this aim, a single-center prospective pharmacoepigenetic study was performed and 50 children who underwent procedural sedation with intravenous ketamine as the only sedative drug were enrolled between October 2019 and November 2022. MiRNA profiling in plasma neural-derived extracellular vesicles was analyzed through next-generation sequencing and measured before treatment with ketamine. Twenty-two patients experienced vomiting or recovery agitation. Among the 16 differentially expressed microRNAs, the upregulated miR-15a-5p and miR-484 targeted genes related to N-methyl-D-aspartate (NMDA) receptor activity, including glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A). Preliminary data confirmed lower GRIN2A levels in patients who developed these events. Downregulated miR-126-3p and miR-24-3p targeted AMPA receptor-associated genes. Functional analyses of gene targets revealed the enrichment of glutamatergic and neurotrophins signaling. Recovery agitation was associated with this network. Vomiting was related to dopaminergic and cholinergic systems. Three miRNAs (miR-18a-3p, miR-484, and miR-548az-5p) were identified as predictive biomarkers (AUC 0.814; 95% CI: 0.632-0.956) for ketamine-induced vomiting and recovery agitation. MicroRNA profiles can predict the development of ketamine-induced vomiting or recovery agitation in children. This study contributes to the understanding of the mechanisms underlying ketamine-induced adverse events.

在儿科急诊环境中,氯胺酮是用于手术镇静和镇痛的镇静剂中安全性最高的一种。然而,氯胺酮可引起呕吐和恢复期躁动。目前还没有研究通过检测微小核糖核酸等表观遗传因素来预测这些不良事件的发生。我们研究了神经元源性细胞外囊泡 microRNA 图谱,以预测氯胺酮诱发的儿童呕吐和恢复期躁动的发生。为此,研究人员开展了一项单中心前瞻性药物表观遗传学研究,并在2019年10月至2022年11月期间招募了50名接受手术镇静的儿童,以静脉注射氯胺酮作为唯一的镇静药物。通过新一代测序分析了血浆神经源细胞外囊泡中的 MiRNA 图谱,并在使用氯胺酮治疗前进行了测量。22名患者出现呕吐或恢复期躁动。在16个差异表达的microRNA中,上调的miR-15a-5p和miR-484靶向与N-甲基-D-天冬氨酸(NMDA)受体活性相关的基因,包括谷氨酸离子型受体NMDA型亚基2A(GRIN2A)。初步数据证实,发生这些事件的患者体内 GRIN2A 水平较低。下调的 miR-126-3p 和 miR-24-3p 针对 AMPA 受体相关基因。对基因靶点的功能分析显示,谷氨酸能和神经营养素信号传导丰富。恢复期躁动与这一网络有关。呕吐与多巴胺能和胆碱能系统有关。三个 miRNA(miR-18a-3p、miR-484 和 miR-548az-5p)被确定为氯胺酮诱发呕吐和恢复期躁动的预测性生物标志物(AUC 0.814;95% CI:0.632-0.956)。微RNA图谱可预测氯胺酮诱发的儿童呕吐或恢复期躁动的发生。这项研究有助于了解氯胺酮诱发不良事件的机制。
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引用次数: 0
Towards Preanalytical Best Practices for Liquid Biopsy Studies: A BLOODPAC Landscape Analysis. 实现液体活检研究的分析前最佳实践:BLOODPAC 前景分析。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-20 DOI: 10.1002/cpt.3416
Christina M Lockwood, Jason D Merker, Elizabeth Bain, Caroline Compton, Robert L Grossman, Donald Johann, Frederick Jones, Gregory Jones, Matthew Kreifels, Suzanne LeBlang, Jerry S H Lee, John Lyle, Jean-Francois Martini, Lauren Saunders, Howard Scher, Stella Somiari, Mark Stewart, Jacob Vinson, Lauren C Leiman

BLOODPAC is a public-private consortium that develops best practices, coordinates clinical and translational research, and manages the BLOODPAC Data Commons to broadly support the liquid biopsy community and accelerate regulatory review to aid patient accessibility. BLOODPAC previously recommended 11 preanalytical minimal technical data elements (MTDEs) for BLOODPAC-sponsored studies and data submitted to BLOODPAC Data Commons. The current landscape analysis evaluates the overlap of the BLOODPAC MTDEs with current best practices, guidelines, and standards documents related to clinical and research liquid biopsy applications. Our findings indicate an existing high degree of concordance among these documents. Where differences exist, the BLOODPAC preanalytical MTDEs can be considered a minimal practicable set for organizations to utilize. These MTDEs were developed following extensive examination of best practices and iterative conversations with the U.S. FDA. BLOODPAC recommends the use of these MTDEs in submissions to data commons and to support liquid biopsy clinical trials and research globally.

BLOODPAC 是一个公私联盟,负责开发最佳实践、协调临床和转化研究,并管理 BLOODPAC 数据共享中心,以广泛支持液体活检社区,加快监管审查,帮助患者获得治疗。BLOODPAC 之前为 BLOODPAC 赞助的研究和提交给 BLOODPAC 数据共享中心的数据推荐了 11 个分析前最小技术数据元素 (MTDE)。当前的概况分析评估了 BLOODPAC MTDE 与当前临床和研究液体活检应用相关的最佳实践、指南和标准文件的重叠情况。我们的研究结果表明,这些文件之间存在高度的一致性。在存在差异的地方,BLOODPAC 分析前 MTDE 可被视为可供各机构使用的最基本实用工具集。这些 MTDE 是在广泛研究最佳实践并与美国 FDA 反复交流后制定的。BLOODPAC 建议在向数据共享中心提交数据时使用这些 MTDE,并在全球范围内支持液体活检临床试验和研究。
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引用次数: 0
Developmental Expression of Drug Transporters and Conjugating Enzymes Involved in Enterohepatic Recycling: Implication for Pediatric Drug Dosing 参与肝内循环的药物转运体和共轭酶的发育表达:对儿科药物剂量的影响
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-19 DOI: 10.1002/cpt.3409
Aarzoo Thakur, Sandhya Subash, Deepak Ahire, Bhagwat Prasad

Around 50% of the drugs used in children have never been tested for safety and efficacy in this vulnerable population. Immature drug elimination pathways can lead to drug toxicity when pediatric doses are determined using empirical methods such as body-surface area or body-weight-normalized adult dosing. In the absence of clinical data, physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to predict drug pharmacokinetics in children. These models utilize developmental physiological data, including age-dependent differences in the abundance of drug-metabolizing enzymes and transporters (DMET), to mechanistically extrapolate adult pharmacokinetic data to children. The reported abundance data of hepatic DMET proteins in subcellular fractions isolated from frozen tissue are prone to high technical variability. Therefore, we carried out the proteomics-based quantification of hepatic drug transporters and conjugating enzymes in 50 pediatric and 8 adult human hepatocyte samples. Out of the 34 studied proteins, 28 showed a significant increase or decrease with age. While MRP6, OAT7, and SULT1E1 were highest in < 1-year-old samples, the abundance of P-gp and UGT1A4 was negligible in < 1-year-old samples and increased significantly after 1 year of age. Incorporation of the age-dependent abundance data in PBPK models can help improve pediatric dose prediction, leading to safer drug pharmacotherapy in children.

用于儿童的药物中约有 50%从未在这一弱势群体中进行过安全性和有效性测试。如果采用体表面积或体重归一化成人剂量等经验方法确定儿科剂量,不成熟的药物消除途径可能会导致药物毒性。在缺乏临床数据的情况下,基于生理学的药代动力学(PBPK)模型已成为预测儿童药物药代动力学的有用工具。这些模型利用发育生理数据,包括药物代谢酶和转运体(DMET)丰度随年龄的差异,从机理上将成人药代动力学数据外推至儿童。已报道的从冷冻组织中分离的亚细胞分馏物中肝脏 DMET 蛋白的丰度数据容易产生较大的技术变异。因此,我们对 50 个儿童和 8 个成人肝细胞样本中的肝脏药物转运体和结合酶进行了基于蛋白质组学的定量分析。在研究的 34 种蛋白质中,有 28 种随着年龄的增长而明显增加或减少。而 MRP6、OAT7 和 SULT1E1 在小儿和成人肝细胞中的含量最高。
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引用次数: 0
Ongoing Pharmacological Developments in SLC6A1 Research & Treatment SLC6A1 研究与治疗中的药物学发展。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-16 DOI: 10.1002/cpt.3413
Melissa B. DeLeeuw, Jacob Tiller, Jing-Qiong Kang, Amber Freed
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引用次数: 0
Getting the Dose Right in Drug Development for Rare Diseases: Barriers and Enablers 在罕见病药物开发过程中正确掌握剂量:障碍与促进因素。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-16 DOI: 10.1002/cpt.3407
Mariam A. Ahmed, Rajesh Krishna, Noha Rayad, Salwa Albusaysi, Amitava Mitra, Elizabeth Shang, Yuen Yi Hon, Bilal AbuAsal, Rana Bakhaidar, Youssef M. Roman, Indranil Bhattacharya, James Cloyd, Munjal Patel, Reena V. Kartha, Islam R. Younis

In the relentless pursuit of optimizing drug development, the intricate process of determining the ideal dosage unfolds. This involves “dose-finding” studies, crucial for providing insights into subsequent registration trials. However, the challenges intensify when tackling rare diseases. The complexity arises from poorly understood pathophysiologies, scarcity of appropriate animal models, and limited natural history understanding. The inherent heterogeneity, coupled with challenges in defining clinical end points, poses substantial challenges, hindering the utility of available data. The small affected population, low disease awareness, and restricted healthcare access compound the difficulty in conducting dose-finding studies. This white paper delves into critical dose selection aspects, focusing on key therapeutic areas, such as oncology, neurology, hepatology, metabolic rare diseases. It also explores dose selection challenges posed by pediatric rare diseases as well as novel modalities, including enzyme replacement therapies, cell and gene therapies, and oligonucleotides. Several examples emphasize the pivotal role of clinical pharmacology in navigating the complexities associated with these diseases and emerging treatment modalities.

在不懈追求优化药物开发的过程中,确定理想剂量的复杂过程不断展开。这就需要进行 "剂量探索 "研究,这对后续的注册试验至关重要。然而,在应对罕见病时,挑战会更加严峻。这种复杂性源于人们对病理生理学的不甚了解、缺乏合适的动物模型以及对自然史的了解有限。固有的异质性,加上临床终点定义方面的挑战,构成了巨大的挑战,阻碍了现有数据的实用性。受影响人群少、对疾病的认知度低、医疗服务受限,这些都增加了开展剂量测定研究的难度。本白皮书深入探讨了关键的剂量选择问题,重点关注肿瘤学、神经病学、肝病学、代谢性罕见病等关键治疗领域。白皮书还探讨了儿科罕见病以及新型疗法(包括酶替代疗法、细胞和基因疗法以及寡核苷酸)带来的剂量选择挑战。多个实例强调了临床药理学在应对与这些疾病和新兴治疗方式相关的复杂问题方面所发挥的关键作用。
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引用次数: 0
New Biomarkers for Renal Transporter-Mediated Drug-Drug Interactions: Metabolomic Effects of Cimetidine, Probenecid, Verapamil, and Rifampin in Humans. 肾脏转运体介导的药物间相互作用的新生物标记物:西米替丁、丙磺舒、维拉帕米和利福平在人体中的代谢作用。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-15 DOI: 10.1002/cpt.3414
Arne Gessner, Jörg König, Pia Wenisch, Markus R Heinrich, Peter Stopfer, Martin F Fromm, Fabian Müller

The inhibition of renal transport proteins organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and organic anion transporters (OAT1, OAT3) causes clinically relevant drug-drug interactions (DDI). Endogenous biomarkers could be used to improve risk prediction of such renal DDIs. While a number of biomarkers for renal DDIs have been described so far, multiple criteria for valid biomarkers have frequently not been investigated, for example, specificity, metabolism, or food effects. Therefore, there is a need for novel biomarkers of renal DDIs. Here, we investigated the global metabolomic effects following the administration of two classical inhibitors of renal transport proteins [cimetidine (OCT2/MATEs), probenecid (OATs)] in human plasma and urine of healthy volunteers. Additionally, we investigated metabolomic effects of two inhibitors of other transporters [verapamil (P-glycoprotein), rifampin (organic anion transporting polypeptides)] as controls. This analysis shows that both cimetidine and probenecid affect compounds involved in caffeine metabolism, carnitines, and sulfates. Hierarchical cluster analysis of the effects of all four inhibitors on endogenous compounds identified multiple promising new sensitive and specific biomarker candidates for OCT2/MATE- or OAT-mediated DDIs. For OCT2/MATEs, 5-amino valeric acid betaine (median log2-fold change of estimated renal elimination: -3.62) presented itself as a promising candidate. For OATs, estimated renal elimination of 7-methyluric acid and cinnamoylglycine (median log2-fold changes -3.10 and -1.92, respectively) was both sensitive and specific. This study provides comprehensive information on metabolomic effects of transport protein inhibition in humans and identifies putative new sensitive and specific biomarkers for renal transporter-mediated DDIs.

肾脏转运蛋白有机阳离子转运蛋白2(OCT2)、多药和毒素挤出蛋白(MATE1、MATE2-K)以及有机阴离子转运蛋白(OAT1、OAT3)的抑制会引起临床相关的药物相互作用(DDI)。内源性生物标志物可用于改善此类肾脏 DDI 的风险预测。虽然迄今为止已经描述了许多肾脏 DDIs 的生物标志物,但有效生物标志物的多种标准往往尚未得到研究,例如特异性、代谢或食物效应。因此,我们需要新的肾脏 DDIs 生物标志物。在此,我们研究了健康志愿者服用两种经典的肾转运蛋白抑制剂[西咪替丁 (OCT2/MATEs)、丙磺舒 (OATs)]后,人体血浆和尿液中的整体代谢组学效应。此外,我们还研究了作为对照组的两种其他转运蛋白抑制剂[维拉帕米(P-糖蛋白)、利福平(有机阴离子转运多肽)]的代谢组学效应。该分析表明,西咪替丁和丙磺舒都会影响参与咖啡因代谢的化合物、肉毒碱和硫酸盐。通过对所有四种抑制剂对内源性化合物的影响进行分层聚类分析,发现了多种有望成为 OCT2/MATE 或 OAT 介导的 DDIs 的新的敏感而特异的候选生物标记物。对于 OCT2/MATEs 而言,5-氨基戊酸甜菜碱(估计肾脏消除量的中位对数2倍变化:-3.62)是一个很有希望的候选物。对于 OATs,7-甲基尿酸和肉桂酰甘氨酸的估计肾排出量(中位数对数2倍变化分别为-3.10和-1.92)既敏感又特异。这项研究提供了有关转运蛋白抑制对人体代谢组学影响的全面信息,并确定了肾脏转运体介导的 DDI 的敏感性和特异性新生物标记物。
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引用次数: 0
Pediatric Rare Diseases Development in the Pharmaceutical Industry: An International Consortium for Innovation and Quality in Pharmaceutical Development, Clinical Pharmacology Leadership Group-Pediatrics Working Group, Rare Diseases Subteam Whitepaper Examining the Current Landscape and Recommendations for the Future 制药业的儿科罕见病开发:国际药物开发创新与质量联合会,临床药理领导小组-儿科工作组,罕见病小组白皮书《当前形势与未来建议》。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-15 DOI: 10.1002/cpt.3422
Rajesh Krishna, Bernard Sebastien, Solange Corriol-Rohou, S. Y. Amy Cheung, Jing Liu, Satyendra Suryawanshi

Many new opportunities surround rare pediatric disease drug development, thanks to key advances in regulatory thinking and in the scientific community. As rare disease drug development brings challenges to the developers in terms of limited understanding of natural history, heterogeneity in drug response, as well as difficulty recruiting patients in pivotal trials, there has never been a greater need for quantitative integration. To understand how International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) member companies approach pediatric rare disease drug development, the rare pediatric subteam of the Clinical Pharmacology Leadership Group (CPLG) sponsored Pediatrics Working Group conducted a baseline survey to assess the four main pillars of this quantitative innovation, namely, biomarkers and surrogate end points, statistical methodologies, model-informed drug development, as well as public–private partnerships. The survey was administered by IQ and yielded 13 evaluable responders from represented companies. This article presents the key findings from this baseline identifying survey, highlighting the key blind spots, and providing insightful expert opinions to address those gaps. In summary, we call an urgent attention to the community on the opportunities to enhance integration and within-industry learnings from this analysis on aspects related to platform studies, end-to-end quantitative integration, and sharing of trial-level placebo data for better understanding of disease progression and more efficient trial designs. We collectively hope that these findings will stimulate discussion and debate around cross-industry sharing and collaboration to better delineate principles and further enhance the efficiency of rare pediatric disease drug development.

由于监管思想和科学界的重大进步,罕见儿科疾病药物开发迎来了许多新机遇。由于罕见病药物开发给开发者带来的挑战包括对自然病史的了解有限、药物反应的异质性以及在关键试验中招募患者的困难,因此现在比以往任何时候都更需要定量整合。为了了解国际药物开发创新与质量联盟(IQ)成员公司如何进行儿科罕见病药物开发,临床药理领导小组(CPLG)赞助的儿科工作组罕见病儿科分小组进行了一次基线调查,以评估这种定量创新的四大支柱,即生物标记物和替代终点、统计方法、模型指导药物开发以及公私合作。该调查由 IQ 公司负责实施,共收到 13 家代表公司的可评估答卷。本文介绍了此次基线识别调查的主要发现,强调了关键盲点,并针对这些差距提出了独到的专家意见。总之,我们呼吁社会各界紧急关注加强整合的机会,并从与平台研究、端到端定量整合以及共享试验级安慰剂数据相关的分析中汲取行业内的经验教训,以便更好地了解疾病进展和更有效地进行试验设计。我们共同希望,这些发现将激发围绕跨行业共享与合作的讨论和辩论,从而更好地界定原则,进一步提高罕见儿科疾病药物开发的效率。
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Clinical Pharmacology & Therapeutics
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