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Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor
Neil L Spector1, Faith C Robertson1, Sarah Bacus2
1Department of Medicine, Duke Cancer Center, Duke University Medical Center, Durham, North Carolina, United States of America.
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.
Insights
Plasma drug levels underestimate tumor concentrations of lapatinib, a targeted cancer therapy. This finding suggests optimizing dosing based on tumor levels is crucial for effective HER receptor inhibition in breast cancer treatment.
Area of Science:
- Pharmacology
- Oncology
- Biochemistry
Background:
- The shift towards targeted cancer therapies necessitates optimizing drug dosing based on biologically effective doses.
- Current methods often use plasma concentrations of tyrosine kinase inhibitors as a surrogate for tumor concentrations.
- Understanding the plasma-tumor drug concentration relationship is critical for effective treatment.
Purpose of the Study:
- To investigate the relationship between lapatinib concentrations in plasma and tumor tissue.
- To assess the impact of lapatinib levels on human epidermal growth factor receptor (HER) phosphorylation in human tumors.
- To compare drug distribution in tumor versus plasma in both preclinical (mouse) and clinical (human) models.
Main Methods:
- Mice with HER2+ breast cancer xenografts were administered lapatinib once or twice daily.
- Drug concentrations were quantified in blood, tumor, liver, and kidney of mice.
- A randomized Phase I clinical trial evaluated steady-state lapatinib levels in plasma and tumor of 28 treatment-naïve HER2+ breast cancer patients receiving different lapatinib doses and schedules.
Main Results:
- Lapatinib concentrations were 4-fold higher in tumors than blood in mice, with a 4-fold longer half-life.
- In patients, tumor lapatinib levels were 6- to 10-fold higher than plasma trough levels, depending on dosing schedule (QD vs. BID).
- HER receptor phosphorylation levels varied with tumor lapatinib concentrations, indicating complex drug effects.
Conclusions:
- Plasma lapatinib concentrations significantly underestimate tumor drug levels.
- Dosing strategies should prioritize achieving effective concentrations at the tumor site to avoid inappropriate dose escalation.
- Further clinical trials are needed to establish optimal dosing for maximal HER receptor inhibition.
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