Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors

doi:10.1007/s40262-016-0427-y

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	Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors
	Yu, Mingming 1,2; Gao, Zhiwei1,2 ; Dai, Xiaojian1,2 ; Gong, Hui 3; Zhang, Lianshan 4; Chen, Xiaoyan1,2 ; Zhong, Da-Fang1,2 ; Sy, Sherwin K. B.5
刊名	CLINICAL PHARMACOKINETICS
	2017-01
卷号	56 期号:1 页码:65-76
ISSN号	0312-5963
DOI	10.1007/s40262-016-0427-y
文献子类	Article
英文摘要	Background and Objectives Apatinib is an oral tyrosine kinase inhibitor approved in China for the treatment of patients with advanced metastatic gastric cancer. The approved dosing schedule is 850 mg once daily. The objective of this study was to develop a population pharmacokinetic (popPK) model of apatinib and determine factors that affect its pharmacokinetics. Methods A popPK model for apatinib was developed using data from 106 individuals, including healthy volunteers and patients with malignant solid tumors. The potential influence of demographic, patient, and laboratory characteristics on oral apatinib pharmacokinetics were investigated in a covariate analysis. The extent of the impact of significant covariates on the exposure of apatinib was evaluated using simulations. Results The final popPK model was a two-compartment model with mixed first- and zero-order absorption and first-order elimination. The population estimates of apparent clearance (CL/F) and apparent volume at steady-state were 57.8 L/h and 112.5 L, respectively. The non-linear dose proportionality in apatinib relative bioavailability was characterized by a sigmoidal maximum effect (E-max) equation wherein the midpoint dose for the decrease in bioavailability was 766 mg. Patients with advanced gastric cancer exhibited lower bioavailability. Cancer patients in general had lower CL/F than healthy volunteers. Simulation results indicated that apatinib exposure in various population groups were impacted by disease and laboratory characteristics. Conclusions The increase in apatinib exposure was less than proportional to dose. The pharmacokinetics of apatinib in gastric cancer patients were significantly different from those in patients with other cancer types. Dosing of apatinib in various cancer subpopulations may require adjustments to optimize efficacy and benefits to patients.
WOS关键词	ADVANCED GASTRIC-CANCER ; BREAST-CANCER ; DOUBLE-BLIND ; PHASE-II ; IN-VITRO ; YN968D1 ; TRIAL ; DISPOSITION ; PERTUZUMAB ; RESISTANCE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ADIS INT LTD
WOS记录号	WOS:000392189700006
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275747]
专题	上海药物代谢研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zhong, Da-Fang; Sy, Sherwin K. B.
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, 501 Haike Rd, Shanghai 201203, Peoples R China; 3.Valpraisso Univ, Dept Math & Stat, Valpraiso, IN USA; 4.Jiangsu Hengrui Pharmaceut Co Ltd, Shanghai, Peoples R China; 5.Univ Estadual Maringa, Dept Stat, Postgrad Program Biostat, Ave Colombo,5790 Bloco E90 Sala 221, BR-87020900 Maringa, Parana, Brazil
推荐引用方式 GB/T 7714	Yu, Mingming,Gao, Zhiwei,Dai, Xiaojian,et al. Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors[J]. CLINICAL PHARMACOKINETICS,2017,56(1):65-76.
APA	Yu, Mingming.,Gao, Zhiwei.,Dai, Xiaojian.,Gong, Hui.,Zhang, Lianshan.,...&Sy, Sherwin K. B..(2017).Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors.CLINICAL PHARMACOKINETICS,56(1),65-76.
MLA	Yu, Mingming,et al."Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors".CLINICAL PHARMACOKINETICS 56.1(2017):65-76.