建立基于生理的体内药代动力学（PBPK）模型研究穿心莲内酯在小鼠体内的药代动力学特征及其在大鼠、犬和人体内的外推。

The Development of a Physiologically Based Pharmacokinetic (PBPK) Model of Andrographolide in Mice and Scaling it up to Rats, Dogs, and Humans.

机构信息

Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, Thailand.

Faculty of Pharmaceutical Sciences Naresuan University, Cosmetics and Natural Products Research Center, Phitsanulok, Thailand.

出版信息

Curr Drug Metab. 2022;23(7):538-552. doi: 10.2174/1389200223666220628095616.

DOI:10.2174/1389200223666220628095616

PMID:35762544

Abstract

BACKGROUND

Andrographolide has a potent antiviral effect in the treatment of coronavirus disease (COVID-19). However, there are no in vivo studies of andrographolide as an anti-COVID-19 treatment.

OBJECTIVE

The study aims to develop a physiologically based pharmacokinetic (PBPK) animal model and scale it up to a human model to predict andrographolide concentrations in the lungs.

METHODS

ADAPT5 (version 5.0.58) was used to establish the PBPK model based on 24 enrolled pharmacokinetic studies.

RESULTS

The perfusion-limited PBPK model was developed in mice and extrapolated to rats, dogs, and humans. The metabolism of andrographolide in humans was described by the Michaelis-Menten equation. The saturation of the metabolism occurred at a high dose (12 g), which could not be used therapeutically. The optimized oral bioavailability in humans was 6.3%. Due to the limit of solubility, the dose-dependent absorption between 20-1000 mg was predicted by GastroPlus®. Using the extrapolated human PBPK model together with the predicted dose-dependent fraction of the dose absorbed that enters the enterocytes by GastroPlus®, the oral dosage of 200 mg q8h of andrographolide would provide a trough level of free andrographolide at a steady state over the reported IC value against SARS-CoV-2 in the lungs for the majority of healthy humans. Based on the reported CC value, toxicity might not occur at the therapeutic dosage.

CONCLUSION

The PBPK model of andrographolide in animals and humans was successfully constructed. Once additional data is available, the model would be needed to recalibrate to gain an understanding of a dose-response relationship and optimization of dosage regimens of andrographolide.

摘要

背景

穿心莲内酯在治疗冠状病毒病（COVID-19）方面具有很强的抗病毒作用。然而，目前尚无穿心莲内酯作为抗 COVID-19 治疗药物的体内研究。

目的

本研究旨在建立一种基于生理学的药代动力学（PBPK）动物模型，并将其扩展到人体模型，以预测穿心莲内酯在肺部的浓度。

方法

使用 ADAPT5（版本 5.0.58）根据 24 项药代动力学研究建立 PBPK 模型。

结果

建立了在小鼠中受限灌注的 PBPK 模型，并外推至大鼠、狗和人体。人体穿心莲内酯的代谢通过米氏方程描述。在高剂量（12 g）下，代谢会饱和，这在治疗上是不可用的。人体口服生物利用度的优化值为 6.3%。由于溶解度的限制，GastroPlus®预测了 20-1000 mg 剂量范围内的剂量依赖性吸收。使用外推的人体 PBPK 模型以及 GastroPlus®预测的吸收进入肠细胞的剂量依赖分数，200 mg q8h 的口服穿心莲内酯剂量将在大多数健康人群中提供报告的 IC 值针对 SARS-CoV-2 在肺部的游离穿心莲内酯的谷水平。基于报告的 CC 值，在治疗剂量下不会发生毒性。