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凝血级联定量系统药理学模型综述:提高可用性的机遇

A Review of Quantitative Systems Pharmacology Models of the Coagulation Cascade: Opportunities for Improved Usability.

作者信息

Chung Douglas, Bakshi Suruchi, van der Graaf Piet H

机构信息

Quantitative Systems Pharmacology, Certara UK Limited, Sheffield S1 2BJ, UK.

Division of Systems Pharmacology and Pharmacy, LACDR, University of Leiden, 2300 RA Leiden, The Netherlands.

出版信息

Pharmaceutics. 2023 Mar 11;15(3):918. doi: 10.3390/pharmaceutics15030918.

Abstract

Despite the numerous therapeutic options to treat bleeding or thrombosis, a comprehensive quantitative mechanistic understanding of the effects of these and potential novel therapies is lacking. Recently, the quality of quantitative systems pharmacology (QSP) models of the coagulation cascade has improved, simulating the interactions between proteases, cofactors, regulators, fibrin, and therapeutic responses under different clinical scenarios. We aim to review the literature on QSP models to assess the unique capabilities and reusability of these models. We systematically searched the literature and BioModels database reviewing systems biology (SB) and QSP models. The purpose and scope of most of these models are redundant with only two SB models serving as the basis for QSP models. Primarily three QSP models have a comprehensive scope and are systematically linked between SB and more recent QSP models. The biological scope of recent QSP models has expanded to enable simulations of previously unexplainable clotting events and the drug effects for treating bleeding or thrombosis. Overall, the field of coagulation appears to suffer from unclear connections between models and irreproducible code as previously reported. The reusability of future QSP models can improve by adopting model equations from validated QSP models, clearly documenting the purpose and modifications, and sharing reproducible code. The capabilities of future QSP models can improve from more rigorous validation by capturing a broader range of responses to therapies from individual patient measurements and integrating blood flow and platelet dynamics to closely represent in vivo bleeding or thrombosis risk.

摘要

尽管有多种治疗出血或血栓形成的方法,但对于这些疗法以及潜在新疗法的效果,仍缺乏全面的定量机制理解。最近,凝血级联反应的定量系统药理学(QSP)模型质量有所提高,能够模拟蛋白酶、辅因子、调节剂、纤维蛋白之间的相互作用以及不同临床场景下的治疗反应。我们旨在回顾关于QSP模型的文献,以评估这些模型的独特能力和可重用性。我们系统地检索了文献和生物模型数据库,回顾了系统生物学(SB)和QSP模型。这些模型的大多数目的和范围都有冗余,只有两个SB模型作为QSP模型的基础。主要有三个QSP模型具有全面的范围,并且在SB和更新的QSP模型之间有系统的联系。最近的QSP模型的生物学范围已经扩大,能够模拟以前无法解释的凝血事件以及治疗出血或血栓形成的药物效果。总体而言,正如之前所报道的,凝血领域似乎存在模型之间联系不清晰以及代码不可重现的问题。未来QSP模型的可重用性可以通过采用经过验证的QSP模型的模型方程、清晰记录目的和修改内容以及共享可重现代码来提高。未来QSP模型的能力可以通过更严格的验证来提高,即从个体患者测量中捕捉更广泛的治疗反应,并整合血流和血小板动力学,以更准确地反映体内出血或血栓形成风险。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e70b/10054658/e118cc05b39a/pharmaceutics-15-00918-g001.jpg

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