title: Prediction of active drug plasma concentrations achieved in cancer patients by pharmacodynamic biomarkers identified from the geo human colon carcinoma xenograft model.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR), a protein tyrosine kinase expressed in many types of human cancers, has been strongly associated with tumor progression. Cetuximab is an IgG(1) anti-EGFR chimeric mouse/human monoclonal antibody that has been approved for the treatment of advanced colon cancer. Using human tumor xenografts grown in nude mice, we have determined the in vivo pharmacodynamic response of cetuximab at efficacious doses. Three pharmacodynamic end points were evaluated: tumoral phospho-EGFR, tumoral mitogen-activated protein kinase (MAPK) phosphorylation, and Ki67 expression.
  
  
  METHODS
  The pharmacodynamic study was conducted in nude mice bearing Geo tumors following a single i.p. administration of 0.25 and 0.04 mg. The tumors were analyzed by immunohistochemistry. The levels of phospho-EGFR were quantitated by an ELISA assay.
  
  
  RESULTS
  At 0.25 mg, phospho-EGFR was maximally inhibited by 91% at 24 hours, whereas the level of inhibition decreased to 72% by 72 hours. At 0.04 mg, the maximum inhibition of phospho-EGFR was 53% at 24 hours, whereas the level of inhibition decreased to 37% by 72 hours. The time course of phospho-EGFR inhibition and recovery seemed to correlate with the pharmacokinetics of cetuximab. Immunohistochemical analysis showed that phospho-MAPK and Ki67 expression were inhibited between 24 and 72 hours at 0.25 and 0.04 mg. A pharmacokinetic/pharmacodynamic model was established and predicted that the plasma concentration of cetuximab required to inhibit 90% of phospho-EGFR was 67.5 mug/mL.
  
  
  CONCLUSIONS
  Phospho-EGFR/phospho-MAPK could be useful clinical biomarkers to assess EGFR inhibition by cetuximab.
authors.affiliation: Oncology Drug Discovery, Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. roger.luo@bms.com
authors.forename: Feng R
authors.initials: FR
authors.lastname: Luo
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Huijin
authors.initials: H
authors.lastname: Dong
authors.forename: Amy
authors.initials: A
authors.lastname: Camuso
authors.forename: Kelly
authors.initials: K
authors.lastname: McGlinchey
authors.forename: Krista
authors.initials: K
authors.lastname: Fager
authors.forename: Christine
authors.initials: C
authors.lastname: Flefleh
authors.forename: David
authors.initials: D
authors.lastname: Kan
authors.forename: Ivan
authors.initials: I
authors.lastname: Inigo
authors.forename: Stephen
authors.initials: S
authors.lastname: Castaneda
authors.forename: Tai W
authors.initials: TW
authors.lastname: Wong
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kramer
authors.forename: Robert
authors.initials: R
authors.lastname: Wild
authors.forename: Francis Y
authors.initials: FY
authors.lastname: Lee
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000096:biosynthesis; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007074:Immunoglobulin G; D019394:Ki-67 Antigen; D066246:ErbB Receptors; D000068818:Cetuximab