Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib

Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The...

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Autores principales:	Hongrui Liu, Yiqun Yu, Nan Guo, Xiaojuan Wang, Bing Han, Xiaoqiang Xiang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	apatinib tyrosine kinase inhibitors (TKIs) physiologically based pharmacokinetic (PBPK) models drug–drug interaction (DDI) drug-disease interaction (DDZI) Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/7b2d55ec8efe48198e55ea62228a25fb
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spelling	oai:doaj.org-article:7b2d55ec8efe48198e55ea62228a25fb2021-11-22T05:16:56ZApplication of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib1663-981210.3389/fphar.2021.780937https://doaj.org/article/7b2d55ec8efe48198e55ea62228a25fb2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.780937/fullhttps://doaj.org/toc/1663-9812Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The present study aimed to evaluate the potential drug–drug interaction (DDI) and drug–disease interaction (DDZI) risks of apatinib in Chinese volunteers.Methods: Modeling and simulation were conducted using Simcyp Simulator. The input parameters required for modeling were obtained from literature research or experiments. Then, the developed physiologically based pharmacokinetic (PBPK) models were applied to evaluate single-dose DDI potential in Chinese healthy volunteers with weak and moderate CYP3A inhibitors, strong CYP2D6 inhibitors, as well as CYP3A4 inducers. The DDZI potential was also predicted in patients with hepatic or renal impairment.Results: The developed PBPK models accurately assessed apatinib pharmacokinetics following single-dose administration in Chinese healthy volunteers and cancer patients. The DDI simulation showed 2–4-fold changes in apatinib exposures by moderate CYP3A4 inhibitors and CYP3A4 inducers. A moderate increase of apatinib exposure (1.25–2-fold) was found with strong CYP2D6 inhibitor. In the DDZI simulation with hepatic impairment, the AUC of apatinib was significantly increased by 2.25-fold and 3.04-fold for Child–Pugh B and Child–Pugh C, respectively, with slightly decreased Cmax by 1.54 and 1.67-fold, respectively.Conclusion: The PBPK models developed in the present study would be highly beneficial to quantitatively predict the pharmacokinetic changes of apatinib under different circumstances, which might be difficult to evaluate clinically, so as to avoid some risks in advance.Hongrui LiuYiqun YuNan GuoXiaojuan WangBing HanXiaoqiang XiangFrontiers Media S.A.articleapatinibtyrosine kinase inhibitors (TKIs)physiologically based pharmacokinetic (PBPK) modelsdrug–drug interaction (DDI)drug-disease interaction (DDZI)Therapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	apatinib tyrosine kinase inhibitors (TKIs) physiologically based pharmacokinetic (PBPK) models drug–drug interaction (DDI) drug-disease interaction (DDZI) Therapeutics. Pharmacology RM1-950
spellingShingle	apatinib tyrosine kinase inhibitors (TKIs) physiologically based pharmacokinetic (PBPK) models drug–drug interaction (DDI) drug-disease interaction (DDZI) Therapeutics. Pharmacology RM1-950 Hongrui Liu Yiqun Yu Nan Guo Xiaojuan Wang Bing Han Xiaoqiang Xiang Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib
description	Aim: Apatinib is an orally administered vascular epidermal growth factor receptor (VEGFR)-tyrosine kinase inhibitors approved for the treatment of advanced gastric adenocarcinoma or gastric esophageal junction adenocarcinoma. Apatinib is predominantly metabolized by CYP3A4/5, followed by CYP2D6. The present study aimed to evaluate the potential drug–drug interaction (DDI) and drug–disease interaction (DDZI) risks of apatinib in Chinese volunteers.Methods: Modeling and simulation were conducted using Simcyp Simulator. The input parameters required for modeling were obtained from literature research or experiments. Then, the developed physiologically based pharmacokinetic (PBPK) models were applied to evaluate single-dose DDI potential in Chinese healthy volunteers with weak and moderate CYP3A inhibitors, strong CYP2D6 inhibitors, as well as CYP3A4 inducers. The DDZI potential was also predicted in patients with hepatic or renal impairment.Results: The developed PBPK models accurately assessed apatinib pharmacokinetics following single-dose administration in Chinese healthy volunteers and cancer patients. The DDI simulation showed 2–4-fold changes in apatinib exposures by moderate CYP3A4 inhibitors and CYP3A4 inducers. A moderate increase of apatinib exposure (1.25–2-fold) was found with strong CYP2D6 inhibitor. In the DDZI simulation with hepatic impairment, the AUC of apatinib was significantly increased by 2.25-fold and 3.04-fold for Child–Pugh B and Child–Pugh C, respectively, with slightly decreased Cmax by 1.54 and 1.67-fold, respectively.Conclusion: The PBPK models developed in the present study would be highly beneficial to quantitatively predict the pharmacokinetic changes of apatinib under different circumstances, which might be difficult to evaluate clinically, so as to avoid some risks in advance.
format	article
author	Hongrui Liu Yiqun Yu Nan Guo Xiaojuan Wang Bing Han Xiaoqiang Xiang
author_facet	Hongrui Liu Yiqun Yu Nan Guo Xiaojuan Wang Bing Han Xiaoqiang Xiang
author_sort	Hongrui Liu
title	Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib
title_short	Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib
title_full	Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib
title_fullStr	Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib
title_full_unstemmed	Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib
title_sort	application of physiologically based pharmacokinetic modeling to evaluate the drug–drug and drug–disease interactions of apatinib
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/7b2d55ec8efe48198e55ea62228a25fb
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Application of Physiologically Based Pharmacokinetic Modeling to Evaluate the Drug–Drug and Drug–Disease Interactions of Apatinib

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