对于SARS-CoV-2重定位而言,德兰丁的定量肺药动力学:一种基于生理学的药动力学建模方法
Furun Wang1,2, Liuhan Dong1, Juanwen Hu1
1State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
二 (TET) 显示出抗SARS-CoV-2 的潜力. 一个基于生理学的药理动力学 (PBPK) 模型证实TET肺部度超过有效值,支持其用于病毒感染的重新用途.
科学领域:
- 药理学 药理学是指药理学的学科.
- 药理动力学 药理动力学
- 药物重用 药物重用
背景情况:
- 二 (TET) 具有传统的用途,并且在体外表现出抗SARS-CoV-2活性.
- 在TET的体外疗效和体内性能之间存在差距.
- 了解TET的药理动力学对于其潜在的治疗应用至关重要.
研究的目的:
- 使用生理学基础的药理动力学 (PBPK) 模型估计TET的自由肺度.
- 为了将体外抗SARS-CoV-2活性与体内疗效联系起来.
- 评估针对SARS-CoV-2的TET重定位的可能性.
主要方法:
- 在老鼠和狗中进行比较性药理动力学研究,以了解物种间的变化.
- 开发和验证一种特定于动物的PBPK模型,并将其转化为人类模型.
- 在口服TET后预测人体血和肺部度.
- 基于自由肺部药物度的抗病毒疗效的评估.
主要成果:
- 系统性TET清除主要通过肝脏代谢.
- 溶酶体捕获TET会影响其分布体积和组织异质性.
- PBPK模型预测未结合的肺TET度 (1.67-1.74μg/mL) 超过了抗SARS-CoV-2活性的体外EC90 (1.52μg/mL).
- 该PBPK模型成功地弥合了体外活动和体外暴露.
结论:
- PBPK建模在预测体内药物暴露和疗效方面是有效的.
- 在临床剂量下,泰特兰德林的肺部度支持其抗病毒潜力.
- TET显示出作为抗SARS-CoV-2治疗剂的重新使用的希望.
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