Insights into drug development with quantitative systems pharmacology: A prospective case study of uncovering hyperkalemia risk in diabetic nephropathy with virtual clinical trials

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Drug Metabolism and Pharmacokinetics Pub Date : 2024-05-09 DOI:10.1016/j.dmpk.2024.101019

Ryuta Saito, Tomohisa Nakada

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引用次数: 0

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.

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用定量系统药理学洞察药物开发：利用虚拟临床试验揭示糖尿病肾病高钾血症风险的前瞻性案例研究

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，如确定治疗药物的作用机制、患者分层以及从机理上理解疾病的进展。在这篇综述文章中，我们通过对 2013 年至 2022 年这 10 年间发表的 QSP 论文进行调查，展示了 QSP 建模应用的现状。我们还介绍了糖尿病肾病患者使用矿物质皮质激素受体拮抗剂（MRAs，肾素-血管紧张素-醛固酮系统抑制剂）治疗高钾血症的风险评估用例，作为后期临床开发的前瞻性模拟。使用 QSP 模型生成糖尿病肾病虚拟患者，以定量评估非甾体类 MRA（非格列酮和阿帕瑞酮）比甾体类 MRA（依普列酮）发生高钾血症的风险更低。在进行大规模临床试验之前，使用 QSP 模型进行前瞻性模拟研究有助于确定临床开发候选药物的优先次序，并验证与风险-效益相关的基于机制的药理学概念。

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来源期刊

Drug Metabolism and Pharmacokinetics 医学-药学

CiteScore

4.80

自引率

9.50%

发文量

审稿时长

69 days

期刊介绍： DMPK publishes original and innovative scientific papers that address topics broadly related to xenobiotics. The term xenobiotic includes medicinal as well as environmental and agricultural chemicals and macromolecules. The journal is organized into sections as follows: - Drug metabolism / Biotransformation - Pharmacokinetics and pharmacodynamics - Toxicokinetics and toxicodynamics - Drug-drug interaction / Drug-food interaction - Mechanism of drug absorption and disposition (including transporter) - Drug delivery system - Clinical pharmacy and pharmacology - Analytical method - Factors affecting drug metabolism and transport - Expression of genes for drug-metabolizing enzymes and transporters - Pharmacogenetics and pharmacogenomics - Pharmacoepidemiology.