title: Population Pharmacokinetic and Covariate Analysis of Apatinib, an Oral Tyrosine Kinase Inhibitor, in Healthy Volunteers and Patients with Solid Tumors.
abstract: 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.
  
  
  
  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.
  
  
  
  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 (Emax) 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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Mingming
authors.initials: M
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Mathematics and Statistics, Valpraisso University, Valpraiso, IN, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.affiliation: Jiangsu Hengrui Pharmaceuticals Co. Ltd., Shanghai, China.
authors.forename: Lianshan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: 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. dfzhong@simm.ac.cn.
authors.forename: Da-Fang
authors.initials: DF
authors.lastname: Zhong
authors.affiliation: 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.kenneth.sy@gmail.com.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002681:China; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012959:Socioeconomic Factors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C553458:apatinib