title: Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.
abstract: OBJECTIVE
  The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER) in human tumors.
  
  
  METHODS
  Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID) with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD) or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.
  
  
  RESULTS
  In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL) for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.
  
  
  CONCLUSIONS
  Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally inhibit HER receptors.
  
  
  BACKGROUND
  
  
  
  BACKGROUND
  NCT00359190.
authors.affiliation: Department of Medicine, Duke Cancer Center, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Neil L
authors.initials: NL
authors.lastname: Spector
authors.affiliation: Department of Medicine, Duke Cancer Center, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Faith C
authors.initials: FC
authors.lastname: Robertson
authors.affiliation: Targeted Molecular Diagnostics/Quintiles, Westmont, Illinois, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bacus
authors.affiliation: Department of Medicine, Duke Cancer Center, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Blackwell
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Smith
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Kelli
authors.initials: K
authors.lastname: Glenn
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Leanne
authors.initials: L
authors.lastname: Cartee
authors.affiliation: Pivot Oncology Consulting, Durham, North Carolina, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Harris
authors.affiliation: PAREXEL International, Durham, North Carolina, United States of America.
authors.forename: Carie L
authors.initials: CL
authors.lastname: Kimbrough
authors.affiliation: Breast Cancer Specialists, Allentown, Pennsylvania, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Gittelman
authors.affiliation: Department of Surgery, University of Miami School of Medicine, Miami, Florida, United States of America.
authors.forename: Eli
authors.initials: E
authors.lastname: Avisar
authors.affiliation: Dallas Surgical Group, Dallas, Texas, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Beitsch
authors.affiliation: GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Koch
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006207:Half-Life; D006801:Humans; D007150:Immunohistochemistry; D000077341:Lapatinib; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation / Q000187:drug effects; D011799:Quinazolines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012372:ROC Curve; D053719:Tandem Mass Spectrometry; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors