计算神经科学和定量系统药理学:支持神经退行性疾病药物开发的强大组合。

IF 2.2 4区 医学 Q3 PHARMACOLOGY & PHARMACY Journal of Pharmacokinetics and Pharmacodynamics Pub Date : 2024-10-01 Epub Date: 2023-07-28 DOI:10.1007/s10928-023-09876-6
Hugo Geerts, Silke Bergeler, William W Lytton, Piet H van der Graaf
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引用次数: 0

摘要

新治疗干预措施的成功临床开发是众所周知的难题,尤其是在神经退行性疾病领域,预测性生物标志物稀缺,功能改善往往基于患者的感知,通过结构化访谈来捕捉。因此,对中枢神经系统疾病治疗干预相关过程的机理建模一直落后于其他疾病适应症,这可能是因为人们认为大脑非常复杂。然而,在本报告中,我们提出了一个论点:将计算神经科学与分子通路定量系统药理学(QSP)建模相结合是一种强大的模拟工具,可提高神经退行性疾病药物开发的成功概率。计算神经科学旨在预测动作电位动力学和神经元回路激活,这些最终与行为变化和临床相关功能结果相关联。这些过程不仅会受到疾病状态的影响,还会受到神经递质相关蛋白的常见基因型变异以及这些患者群体经常服用的精神活性药物的影响。分子通路的定量系统药理学(QSP)建模可以模拟痴呆症的关键病理驱动因素,如蛋白质聚集和神经炎症反应。它们通常会影响神经递质平衡和电压门控离子通道,或导致线粒体功能障碍,最终导致动作电位动力学和临床读数的变化。将这两种建模方法结合起来,可以更好地了解活跃在人类病变大脑中的许多非线性药效学过程。实际应用包括在联合疗法中合理选择最佳剂量,识别更有可能对治疗产生反应的受试者,根据用药、疾病状态和常见基因型变异对治疗组进行更均衡的分层,以及重新分析小型临床试验以发现可能的临床信号。最终,这将提高将新疗法用于合适患者群体的成功率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Computational neurosciences and quantitative systems pharmacology: a powerful combination for supporting drug development in neurodegenerative diseases.

Successful clinical development of new therapeutic interventions is notoriously difficult, especially in neurodegenerative diseases, where predictive biomarkers are scarce and functional improvement is often based on patient's perception, captured by structured interviews. As a consequence, mechanistic modeling of the processes relevant to therapeutic interventions in CNS disorders has been lagging behind other disease indications, probably because of the perceived complexity of the brain. However in this report, we develop the argument that a combination of Computational Neurosciences and Quantitative Systems Pharmacology (QSP) modeling of molecular pathways is a powerful simulation tool to enhance the probability of successful drug development for neurodegenerative diseases. Computational Neurosciences aims to predict action potential dynamics and neuronal circuit activation that are ultimately linked to behavioral changes and clinically relevant functional outcomes. These processes can not only be affected by the disease state, but also by common genotype variants on neurotransmitter-related proteins and the psycho-active medications often prescribed in these patient populations. Quantitative Systems Pharmacology (QSP) modeling of molecular pathways allows to simulate key pathological drivers of dementia, such as protein aggregation and neuroinflammatory responses. They often impact neurotransmitter homeostasis and voltage-gated ion-channels or lead to mitochondrial dysfunction, ultimately leading to changes in action potential dynamics and clinical readouts. Combining these two modeling approaches can lead to better actionable understanding of the many non-linear pharmacodynamic processes active in the human diseased brain. Practical applications include a rational selection of the optimal doses in combination therapies, identification of subjects more likely to respond to treatment, a more balanced stratification of treatment arms in terms of comedications, disease status and common genotype variants and re-analysis of small clinical trials to uncover a possible clinical signal. Ultimately this will lead to a higher success rate of bringing new therapeutics to the right patient populations.

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来源期刊
CiteScore
4.90
自引率
4.00%
发文量
39
审稿时长
6-12 weeks
期刊介绍: Broadly speaking, the Journal of Pharmacokinetics and Pharmacodynamics covers the area of pharmacometrics. The journal is devoted to illustrating the importance of pharmacokinetics, pharmacodynamics, and pharmacometrics in drug development, clinical care, and the understanding of drug action. The journal publishes on a variety of topics related to pharmacometrics, including, but not limited to, clinical, experimental, and theoretical papers examining the kinetics of drug disposition and effects of drug action in humans, animals, in vitro, or in silico; modeling and simulation methodology, including optimal design; precision medicine; systems pharmacology; and mathematical pharmacology (including computational biology, bioengineering, and biophysics related to pharmacology, pharmacokinetics, orpharmacodynamics). Clinical papers that include population pharmacokinetic-pharmacodynamic relationships are welcome. The journal actively invites and promotes up-and-coming areas of pharmacometric research, such as real-world evidence, quality of life analyses, and artificial intelligence. The Journal of Pharmacokinetics and Pharmacodynamics is an official journal of the International Society of Pharmacometrics.
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