title: Population pharmacokinetics of a HER2 tyrosine kinase inhibitor CP-724,714 in patients with advanced malignant HER2 positive solid tumors.
abstract: OBJECTIVE
  To develop a population pharmacokinetic (popPK) model for CP-724,714, a novel HER2 tyrosine kinase inhibitor is under development for the treatment of advanced HER2 positive cancers.
  
  
  METHODS
  Concentration-time data (n = 484) from 30 cancer patients receiving daily oral CP-724,714 at doses of 250 mg QD, 250 mg BID, 250 mg TID, and 400 mg BID in 21-day cycles in an open label First-in-Human dose-escalation study were evaluated. Serum concentrations of CP-724,714 were obtained after single dose and at steady state. Nonlinear mixed effect analysis in NONMEM using first order conditional estimation with interaction (FOCEI) was performed. The effect of covariates was assessed. Diagnostic plots, decrease of objective function value (>7.8), bootstrapping, and predictive check were used as model selection criteria.
  
  
  RESULTS
  A 2-compartment first-order absorption pharmacokinetic (PK) model with inter-subject variability (ISV) on the apparent oral elimination clearance (CL/F), apparent central volume of distribution (V1/F), apparent peripheral volume of distribution (V2/F), and first-order oral absorption rate constant (ka), interoccasion variability (IOV) on CL/F, and body weight (WT) as covariate on CL/F was developed. There was no evidence of dose-dependent and/or time-dependent PK. CL/F increased with increasing WT. The ISV of CL/F was reduced by approximately 20% with WT as a covariate. Age, race, and liver metastasis did not influence CP-724,714 disposition.
  
  
  CONCLUSIONS
  A popPK model was developed that adequately described the pharmacokinetics of CP-724,714. WT was identified as a covariate on CL/F that reduced ISV and improved model performance. Future studies will further assess the importance of WT as a pharmacokinetic covariate. The proposed popPK model can be used to simulate CP-724,714 Phase 2/3 trials.
authors.affiliation: Department of Clinical Pharmacology, Pfizer Global Research and Development, 50 Pequot Avenue MS6025-A3238, New London, CT 06320, USA. feng.guo@pfizer.com
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Letrent
authors.forename: Amarnath
authors.initials: A
authors.lastname: Sharma
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001835:Body Weight; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary; D008875:Middle Aged; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017711:Nonlinear Dynamics; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C521104:2-methoxy-N-(3-(4-((3-methyl-4-((6-methyl-3-pyridinyl)oxy)phenyl)amino)-6-quinazolinyl)-2-propenyl)acetamide