Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors

doi:10.2147/DDDT.S237301

	Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors
	Zhu, Yun-Ting 2; Teng, Zan 1,3; Zhang, Yi-Fan 2; Li, Wei 2; Guo, Li-Xia 2; Liu, Yun-Peng 1,3; Qu, Xiu-Juan 1,3; Wang, Quan-Ren 4; Mao, Si-Yuan 4; Chen, Xiao-Yan 2
刊名	DRUG DESIGN DEVELOPMENT AND THERAPY
	2020
卷号	14 页码:1963-1970
关键词	apatinib drug-drug interaction CYP3A4 CYP2C9 nifedipine warfarin
ISSN号	1177-8881
DOI	10.2147/DDDT.S237301
通讯作者	Zhang, Yi-Fan(yfzhang@simm.ac.cn) ; Zhong, Da-Fang(dfzhong@simm.ac.cn)
英文摘要	Background and Purpose: Apatinib is a small-molecule tyrosine kinase inhibitor for the treatment of recurrent or progressive advanced-stage gastric adenocarcinoma or gastroeso-phageal junction cancer. The in vitro inhibition studies suggested that apatinib exerted potent inhibition on CYP3A4 and CYP2C9. To evaluate the potential of apatinib as a perpetrator in CYP450-based drug-drug interactions in vivo, nifedipine and warfarin were, respectively, selected in the present study as the probe substrates of CYP3A4 and CYP2C9 for clinical drug-drug interaction studies. Since hypertension and thrombus are common adverse effects of vascular targeting anticancer agents, nifedipine and warfarin are usually coadministered with apatinib in clinical practice. Methods: A single-center, open-label, single-arm, and self-controlled trial was conducted in patients with advanced solid tumors. The patients received a single dose of 30 mg nifedipine on Day 1/14 and a single dose of 3 mg warfarin on Day 3/16. On Day 9-21, the subjects received a daily dose of 750 mg apatinib, respectively. The pharmacokinetics of nifedipine and warfarin in the absence or presence of apatinib was, respectively, investigated. Results: Compared with the single oral administration, coadministration with apatinib contributed to the significant increases of AUC(0) (48)h and C-max of nifedipine by 83% (90% confidence interval [CI] 1.46-2.31) and 64% (90% CI 1.34-2.01), respectively. Similarly, coadministration with apatinib contributed to the significant increases of AUC(0-t) and C-max of S-warfarin by 92% (90% CI 1.68-2.18) and 24% (90% CI 1.10-1.39), respectively. Conclusion: Concomitant apatinib administration resulted in significant increases in systemic exposure to nifedipine and S-warfarin. Owing to the risk of pharmacokinetic drug-drug interactions based on CYP3A4/CYP2C9 inhibition by apatinib, caution is advised in the concurrent use of apatinib with either CYP2C9 or CYP3A4 substrates.
WOS关键词	DRUG-DRUG INTERACTIONS ; S-WARFARIN ; CLEARANCE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	DOVE MEDICAL PRESS LTD
WOS记录号	WOS:000534380400001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279997]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Yi-Fan; Zhong, Da-Fang
作者单位	1.China Med Univ, Dept Med Oncol, Hosp 1, Shenyang, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China 3.China Med Univ, Key Lab Anticanc Drugs & Biotherapy Liaoning Prov, Hosp 1, Shenyang, Peoples R China 4.Jiangsu Hengrui Med Co Ltd, Dept Clin Res & Dev, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Yun-Ting,Teng, Zan,Zhang, Yi-Fan,et al. Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors[J]. DRUG DESIGN DEVELOPMENT AND THERAPY,2020,14:1963-1970.
APA	Zhu, Yun-Ting.,Teng, Zan.,Zhang, Yi-Fan.,Li, Wei.,Guo, Li-Xia.,...&Zhong, Da-Fang.(2020).Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors.DRUG DESIGN DEVELOPMENT AND THERAPY,14,1963-1970.
MLA	Zhu, Yun-Ting,et al."Effects of Apatinib on the Pharmacokinetics of Nifedipine and Warfarin in Patients with Advanced Solid Tumors".DRUG DESIGN DEVELOPMENT AND THERAPY 14(2020):1963-1970.