Purpose Lapatinib, a small molecule EGFR/HER2 inhibitor, has limited effect on outgrowth of HER2+ brain metastases in preclinical and clinical trials. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following 14C-lapatinib administration (100 mg/kg p.o. or 10 mg/kg, i.v.) to mice with MDA-MD-231-BR-HER2 brain metastases of breast cancer. Methods Drug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography. Results 14C-Lapatinib concentration varied among brain metastases and correlated with altered blood-tumor barrier permeability. On average, brain metastasis concentration was 7–9-fold greater than surrounding brain tissue at 2 and 12 hours after oral administration. However, average lapatinib concentration in brain metastases was still only 10–20% of those in peripheral metastases. Only in a subset of brain lesions (17%) did lapatinib concentration approach that of systemic metastases. No evidence was found of lapatinib resistance in tumor cells remaining in brain after lapatinib treatment. Conclusions Results show that lapatinib distribution to brain metastases of breast cancer is restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies within and between tumors.

This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.

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