Abstract：
The quantitative systems pharmacology (QSP) approach is widely applied to address various essential questions in drug discovery and development, such as identification of the mechanism of action of a therapeutic agent, patient stratification, and the mechanistic understanding of the progression of disease. In this review article, we show the current landscape of the application of QSP modeling using a survey of QSP publications over 10 years from 2013 to 2022. We also present a use case for the risk assessment of hyperkalemia in patients with diabetic nephropathy treated with mineralocorticoid receptor antagonists (MRAs, renin-angiotensin-aldosterone system inhibitors), as a prospective simulation of late clinical development. A QSP model for generating virtual patients with diabetic nephropathy was used to quantitatively assess that the nonsteroidal MRAs, finerenone and apararenone, have a lower risk of hyperkalemia than the steroidal MRA, eplerenone. Prospective simulation studies using a QSP model are useful to prioritize pharmaceutical candidates in clinical development and validate mechanism-based pharmacological concepts related to the risk-benefit, before conducting large-scale clinical trials.
摘要：
定量系统药理学（QSP）方法被广泛应用于解决药物发现和开发中的各种基本问题。例如识别治疗剂的作用机制，患者分层,以及对疾病进展的机械理解。在这篇评论文章中，从2013年到2022年，我们使用对QSP出版物的调查显示了QSP建模应用的现状。我们还提供了一个使用盐皮质激素受体拮抗剂治疗的糖尿病肾病患者高钾血症风险评估的用例（MRA，肾素-血管紧张素-醛固酮系统抑制剂），作为后期临床发展的前瞻性模拟。用于生成糖尿病肾病虚拟患者的QSP模型用于定量评估非甾体MRA，Finerenone和apararenone,高钾血症的风险比类固醇MRA低，eplerenone.使用QSP模型的前瞻性模拟研究有助于在临床开发中优先考虑候选药物，并验证与风险-收益相关的基于机制的药理学概念。在进行大规模临床试验之前。
