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

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Abstract

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.

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Authors and Affiliations

  1. State Key Laboratory of Drug Research and Center for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China

    Mingming Yu, Zhiwei Gao, Xiaojian Dai, Xiaoyan Chen & Da-Fang Zhong

  2. Department of Mathematics and Statistics, Valpraisso University, Valpraiso, IN, USA

    Hui Gong

  3. Jiangsu Hengrui Pharmaceuticals Co. Ltd., Shanghai, China

    Lianshan Zhang

  4. Post-Graduate Program in Biostatistics, Department of Statistics, State University of Maringá, Avenida Colombo, 5790 Bloco E90-sala 221, Maringá, PR, CEP 87.020-900, Brazil

    Sherwin K. B. Sy

Authors
  1. Mingming Yu
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  2. Zhiwei Gao
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  3. Xiaojian Dai
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  4. Hui Gong
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  5. Lianshan Zhang
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  6. Xiaoyan Chen
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  7. Da-Fang Zhong
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  8. Sherwin K. B. Sy
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Corresponding authors

Correspondence to Da-Fang Zhong or Sherwin K. B. Sy.

Ethics declarations

Compliance with Ethical Standards

All studies were conducted in accordance with the Declaration of Helsinki and all clinical protocols and amendments were approved by independent ethics committees. All participants provided written informed consent.

Disclosure of potential conflicts of interest

L. Z. is an employee of Jiangsu Hengrui Pharmaceuticals. D. F. Z. received consulting honorarium from Jiangsu Hengrui. M. Y., S. K. B. S., Z. G., X. D., H. G., and X. C. have no conflicts of interest that are directly relevant to the content of this study.

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Yu, M., Gao, Z., Dai, X. et al. Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors. Clin Pharmacokinet 56, 65–76 (2017). https://doi.org/10.1007/s40262-016-0427-y

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  • DOI: https://doi.org/10.1007/s40262-016-0427-y

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