Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor

PLoS One. 2015 Nov 16;10(11):e0142845. doi: 10.1371/journal.pone.0142845. eCollection 2015.

Abstract

Purpose: 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.

Experimental design: 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.

Conclusion: 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.

Clinical trial registration: NCT00359190.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Animals
  • Antineoplastic Agents / blood*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use
  • Area Under Curve
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Drug Administration Schedule
  • Drug Dosage Calculations
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Female
  • Half-Life
  • Humans
  • Immunohistochemistry
  • Lapatinib
  • Mice
  • Mice, SCID
  • Phosphorylation / drug effects
  • Quinazolines / blood*
  • Quinazolines / pharmacokinetics
  • Quinazolines / therapeutic use
  • ROC Curve
  • Tandem Mass Spectrometry
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Quinazolines
  • Lapatinib
  • ErbB Receptors

Associated data

  • ClinicalTrials.gov/NCT00359190

Grant support

Funding for this study was provided by GSK. Editorial support in the form of development of the first draft, editorial suggestions to draft revisions, assembling tables/figures, collating author comments and referencing was provided by Guissou Dabiri, PhD, and was funded by GSK. Quintiles, GlaxoSmithKline, Pivot Oncology Consulting and Dallas Surgical Group provided support in the form of salaries for authors SB, DAS, KG, LC, KMK, JH and PB respectively, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.