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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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引用次数: 0
Population Pharmacokinetics of Trimethoprim/Sulfamethoxazole: Dosage Optimization for Patients with Renal Insufficiency or Receiving Continuous Renal Replacement Therapy. 曲美布汀/磺胺甲噁唑的群体药代动力学:肾功能不全或接受持续肾脏替代疗法患者的剂量优化。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-15 DOI: 10.1002/cpt.3421
Emiel Leegwater, Lauren Baidjoe, Erik B Wilms, Leo G Visser, Daniel J Touw, Brenda C M de Winter, Mark G J de Boer, Judith van Paassen, Charlotte H S B van den Berg, Joffrey van Prehn, Teun van Gelder, Dirk Jan A R Moes

The goal of the study was to describe the population pharmacokinetics of trimethoprim, sulfamethoxazole, and N-acetyl sulfamethoxazole in hospitalized patients. Furthermore, this study used the model to optimize dosing regimens of cotrimoxazole for Pneumocystis jirovecii pneumonia and in patients with renal insufficiency or with continuous renal replacement therapy (CRRT). This was a retrospective multicenter observational cohort study based on therapeutic drug monitoring (TDM) data from hospitalized patients treated with cotrimoxazole. We developed two population pharmacokinetic (POPPK) models: a model of trimethoprim and an integrated model with both sulfamethoxazole and N-acetyl sulfamethoxazole concentrations. Monte Carlo simulations were performed to determine the optimal dosing regimen. A total of 348 measurements from 168 patients were available. The estimated glomerular filtration rate (eGFR) and CRRT were included as covariates on the clearance of all three compounds. Cotrimoxazole TID 1,920 mg and b.i.d. 2,400 mg led to sufficient exposure for infections with P. jirovecii in patients without renal insufficiency. To reach equivalent exposure, a dose reduction of 33.3% is needed in patients with an eGFR of 10 mL/minute/1.73 m2 and of 16.7% for an eGFR of 30 mL/minute/1.73 m2. N-acetyl sulfamethoxazole accumulates in patients with a reduced eGFR. CRRT increased the clearance of sulfamethoxazole, but not trimethoprim or N-acetyl sulfamethoxazole, compared with the median clearance in the population. Doubling the sulfamethoxazole dose is needed for patients on CRRT to reach equivalent exposure.

该研究的目的是描述住院病人体内曲美布林、磺胺甲噁唑和 N-乙酰磺胺甲噁唑的群体药代动力学。此外,该研究还利用该模型优化了治疗肺孢子虫肺炎和肾功能不全或接受持续肾脏替代疗法(CRRT)患者的复方新诺明剂量方案。这是一项基于使用复方新诺明治疗的住院患者的治疗药物监测(TDM)数据进行的回顾性多中心观察队列研究。我们建立了两个群体药代动力学(POPPK)模型:一个是三甲氧苄啶模型,另一个是同时包含磺胺甲噁唑和 N-乙酰磺胺甲噁唑浓度的综合模型。通过蒙特卡罗模拟来确定最佳用药方案。共获得了 168 名患者的 348 次测量结果。估算的肾小球滤过率(eGFR)和 CRRT 被列为三种化合物清除率的协变量。在无肾功能不全的患者中,复方新诺明 TID 1,920 毫克和 b.i.d. 2,400 毫克的剂量对感染 P. jirovecii 有足够的暴露量。为达到同等暴露量,eGFR 为 10 mL/minute/1.73 m2 的患者需要将剂量减少 33.3%,eGFR 为 30 mL/minute/1.73 m2 的患者需要将剂量减少 16.7%。N-acetyl 磺胺甲噁唑会在 eGFR 降低的患者体内蓄积。与人群的中位清除率相比,CRRT 增加了磺胺甲噁唑的清除率,但没有增加三甲氧苄啶或 N-乙酰磺胺甲噁唑的清除率。接受 CRRT 治疗的患者需要将磺胺甲噁唑的剂量增加一倍,才能达到相同的暴露量。
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引用次数: 0
Regulatory Pathways for Qualification and Acceptance of Digital Health Technology-Derived Clinical Trial Endpoints: Considerations for Sponsors. 数字医疗技术衍生临床试验终点的资格认证和验收监管途径:申办者的注意事项。
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-15 DOI: 10.1002/cpt.3398
Jessie P Bakker, Elena S Izmailova, Aude Clement, Steven Hoffmann, Christopher Leptak, Joseph P Menetski, John A Wagner

Despite widespread interest and substantial investment in the adoption of sensor-based digital health technologies (sDHTs) for remote data capture in drug development trials, no drug has been approved based on an sDHT-derived primary endpoint in the United States (US). One reason for this lack of advancement is the complexity of obtaining regulatory endorsement for those endpoints within current US regulatory pathways. The goal of our review is to describe the two choices currently available to pharmaceutical study Sponsors: (i) they may navigate the traditional route of compiling the evidence to support the sDHT-derived endpoint in their investigational new drug (IND) application, requiring specific expertise and substantial resources; or (ii) they may navigate the drug development tool (DDT) pathway with the goal of qualifying their sDHT-derived endpoint as a biomarker or clinical outcome assessment applicable to a broader context of use (COU), either alone or as part of a partnership or consortium. We describe the nuances of each pathway; the evidentiary requirements for supporting an sDHT-derived endpoint and the technology used to capture it; and the impact that an sDHT's regulatory status may have on a Sponsor's decision to use it for data capture. By systematically comparing the IND and DDT pathways, our over-arching goals are to support the increasing deployment of sDHTs within the clinical research setting and help advance regulatory science in the field of digital medicine.

尽管在药物开发试验中采用基于传感器的数字健康技术(sDHTs)进行远程数据采集受到了广泛关注,并投入了大量资金,但在美国,还没有一种药物根据基于 sDHTs 的主要终点获得批准。缺乏进展的原因之一是这些终点在美国现行监管途径中获得监管认可的复杂性。我们综述的目的是描述制药研究申办者目前有两种选择:(i)他们可以选择传统的途径,即汇编证据以支持其研究性新药 (IND) 申请中的 sDHT 衍生终点,这需要特定的专业知识和大量的资源;或者 (ii) 他们可以选择药物开发工具 (DDT) 途径,目的是将其 sDHT 衍生终点鉴定为生物标记物或临床结果评估,适用于更广泛的使用环境 (COU),可以单独使用,也可以作为合作伙伴或联合体的一部分使用。我们描述了每种途径的细微差别;支持 sDHT 衍生终点的证据要求和用于捕获该终点的技术;以及 sDHT 的监管地位可能对申办者决定是否将其用于数据捕获的影响。通过系统比较 IND 和 DDT 途径,我们的总体目标是支持在临床研究环境中越来越多地部署 sDHT,并帮助推进数字医学领域的监管科学。
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引用次数: 0
Effects of Sacubitril/Valsartan on Survival in Patients with Heart Failure and Significant Valvular Heart Disease. 萨库比特利/缬沙坦对心力衰竭合并严重瓣膜性心脏病患者生存期的影响
IF 6.3 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-08-15 DOI: 10.1002/cpt.3417
Donna Shu-Han Lin, Ying-Ting Chao, Shu-Lin Chuang, Jen-Kuang Lee, Ting-Tse Lin, Lung-Chun Lin, Kuan-Chih Huang, Juey-Jen Hwang

Although the benefits of sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) are well established, patients with hemodynamically significant mitral regurgitation (MR) were excluded from pivotal trials. We aimed to assess the effects of sacubitril/valsartan on survival in patients with HFrEF and concomitant significant MR. All patients from a single center who underwent echocardiography between June 2008 and December 2020, with a left ventricular ejection fraction (LVEF) of less than 40% and hemodynamically significant MR were recruited. Patients were categorized according to drug use and year of the index echocardiogram into the angiotensin receptor/neprilysin inhibitor (ARNI), non-ARNI before 2017, and non-ARNI after 2017 groups. Patients in the ARNI and non-ARNI after 2017 groups were compared directly, whereas patients in the non-ARNI before 2017 group were matched to the ARNI group in a 3:1 ratio. The outcome of interest was all-cause mortality. Death was compared between the groups using univariate and multivariate Cox proportional hazard models. After exclusion by criteria and matching, there remained 610 patients in the ARNI group, 434 in the non-ARNI after 2017 group, and 1,722 in the non-ARNI before 2017 group. During follow-up, all-cause mortality was significantly lower in the ARNI group compared with both non-ARNI after 2017 and non-ARNI before 2017 groups. Multivariate analysis of both pairs of comparison between groups found the use of ARNI to be significantly associated with increased survival. In patients with HFrEF and concomitant significant MR, treatment with sacubitril/valsartan was associated with lower risks of all-cause death.

尽管沙库比特利/缬沙坦对射血分数降低型心力衰竭(HFrEF)的疗效已得到公认,但有明显二尖瓣反流(MR)的患者却被排除在关键试验之外。我们旨在评估沙库比特利/缬沙坦对射血分数减低型心力衰竭并伴有明显二尖瓣反流患者生存期的影响。我们招募了在 2008 年 6 月至 2020 年 12 月期间接受超声心动图检查、左心室射血分数(LVEF)小于 40% 并伴有血流动力学显著 MR 的单个中心的所有患者。根据药物使用情况和索引超声心动图的年份将患者分为血管紧张素受体/肾素抑制剂(ARNI)组、2017 年前非 ARNI 组和 2017 年后非 ARNI 组。ARNI组和2017年后非ARNI组患者直接进行比较,而2017年前非ARNI组患者则按3:1的比例与ARNI组进行匹配。关注的结果是全因死亡率。采用单变量和多变量 Cox 比例危险模型对各组之间的死亡情况进行比较。按标准和配对排除后,ARNI 组仍有 610 名患者,2017 年后非 ARNI 组有 434 名患者,2017 年前非 ARNI 组有 1722 名患者。在随访期间,ARNI 组的全因死亡率明显低于 2017 年后非 ARNI 组和 2017 年前非 ARNI 组。对两组间的对比进行多变量分析后发现,使用ARNI与生存率的提高有显著相关性。在高频低氧血症(HFrEF)和伴有明显 MR 的患者中,使用沙库比妥/缬沙坦治疗与较低的全因死亡风险相关。
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Clinical Pharmacology & Therapeutics
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