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

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

Author information

1
Department of Medicine, Duke Cancer Center, Duke University Medical Center, Durham, North Carolina, United States of America.
2
Targeted Molecular Diagnostics/Quintiles, Westmont, Illinois, United States of America.
3
GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America.
4
Pivot Oncology Consulting, Durham, North Carolina, United States of America.
5
PAREXEL International, Durham, North Carolina, United States of America.
6
Breast Cancer Specialists, Allentown, Pennsylvania, United States of America.
7
Department of Surgery, University of Miami School of Medicine, Miami, Florida, United States of America.
8
Dallas Surgical Group, Dallas, Texas, United States of America.

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.

TRIAL REGISTRATION:

CLINICAL TRIAL REGISTRATION:

NCT00359190.

PMID:
26571496
PMCID:
PMC4646457
DOI:
10.1371/journal.pone.0142845
[Indexed for MEDLINE]
Free PMC Article

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