Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck Research Laboratories, West Point, PA, USA.
Impact Analytical, Midland, MI, USA.
Adv Exp Med Biol. 2019;1140:435-449. doi: 10.1007/978-3-030-15950-4_25.
Advances in mass spectrometry, proteomics, protein bioanalytical approaches, and biochemistry have led to a rapid evolution and expansion in the area of mass spectrometry-based biomarker discovery and development. The last decade has also seen significant progress in establishing accepted definitions, guidelines, and criteria for the analytical validation, acceptance and qualification of biomarkers. These advances have coincided with a decreased return on investment for pharmaceutical research and development and an increasing need for better early decision making tools. Empowering development teams with tools to measure a therapeutic interventions impact on disease state and progression, measure target engagement and to confirm predicted pharmacodynamic effects is critical to efficient data-driven decision making. Appropriate implementation of a biomarker or a combination of biomarkers can enhance understanding of a drugs mechanism, facilitate effective translation from the preclinical to clinical space, enable early proof of concept and dose selection, and increases the efficiency of drug development. Here we will provide descriptions of the different classes of biomarkers that have utility in the drug development process as well as review specific, protein-centric, mass spectrometry-based approaches for the discovery of biomarkers and development of targeted assays to measure these markers in a selective and analytically precise manner.
质谱学、蛋白质组学、蛋白质生物分析方法和生物化学的进步，使得基于质谱的生物标志物发现和开发领域迅速发展和扩展。过去十年，在为生物标志物的分析验证、接受和资格建立公认的定义、指南和标准方面也取得了重大进展。这些进展恰逢制药研发投资回报下降，以及对更好的早期决策工具的需求增加。为研发团队提供工具，以衡量治疗干预对疾病状态和进展的影响，衡量目标参与度并确认预测的药效学效应，对于高效的数据驱动决策至关重要。适当实施生物标志物或生物标志物组合可以增强对药物机制的理解，促进从临床前到临床的有效转化，实现早期概念验证和剂量选择，并提高药物开发的效率。在这里，我们将描述在药物开发过程中具有实用价值的不同类别的生物标志物，并回顾特定的、基于蛋白质的、基于质谱的方法，用于发现生物标志物和开发靶向测定法，以选择性和分析精确的方式测量这些标志物。
