研究Alirocumab和降胆固醇疗法对血脂和斑块特征影响的定量系统药理学平台。

Gene regulation and systems biology Pub Date : 2017-06-22 eCollection Date: 2017-01-01 DOI:10.1177/1177625017710941
Jeffrey E Ming, Ruth E Abrams, Derek W Bartlett, Mengdi Tao, Tu Nguyen, Howard Surks, Katherine Kudrycki, Ananth Kadambi, Christina M Friedrich, Nassim Djebli, Britta Goebel, Alex Koszycki, Meera Varshnaya, Joseph Elassal, Poulabi Banerjee, William J Sasiela, Michael J Reed, Jeffrey S Barrett, Karim Azer
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引用次数: 12

摘要

低密度脂蛋白胆固醇(LDL-C)的降低与心血管疾病风险的降低有关。Alirocumab是一种蛋白转化酶枯草素/kexin 9型(PCSK9)抗体,可显著降低LDL-C。在这里,我们报告了一种定量系统药理学(QSP)模型的发展,该模型整合了外周和肝脏胆固醇代谢以及PCSK9功能,以检查alirocumab和其他降脂疗法(包括他汀类药物)的作用机制。该模型预测LDL-C和其他脂类的变化,与在alirocumab和其他治疗的单一或联合治疗的临床试验中观察到的效果一致。研究人员还开发了一个探索性模型来检查脂质水平对斑块动力学的影响。QSP平台的进一步开发和鉴定可能支持PCSK9抑制剂和脂质调节药物的剂量优化和临床试验设计。它也可以提高我们对影响不同表型血脂异常和心血管疾病治疗反应的因素的理解。
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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A Quantitative Systems Pharmacology Platform to Investigate the Impact of Alirocumab and Cholesterol-Lowering Therapies on Lipid Profiles and Plaque Characteristics.

Reduction in low-density lipoprotein cholesterol (LDL-C) is associated with decreased risk for cardiovascular disease. Alirocumab, an antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduces LDL-C. Here, we report development of a quantitative systems pharmacology (QSP) model integrating peripheral and liver cholesterol metabolism, as well as PCSK9 function, to examine the mechanisms of action of alirocumab and other lipid-lowering therapies, including statins. The model predicts changes in LDL-C and other lipids that are consistent with effects observed in clinical trials of single or combined treatments of alirocumab and other treatments. An exploratory model to examine the effects of lipid levels on plaque dynamics was also developed. The QSP platform, on further development and qualification, may support dose optimization and clinical trial design for PCSK9 inhibitors and lipid-modulating drugs. It may also improve our understanding of factors affecting therapeutic responses in different phenotypes of dyslipidemia and cardiovascular disease.

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