• Kunal S Taskar, Vinay Rudraraju, Rajendar K Mittapalli, Ramakrishna Samala, Helen R Thorsheim, Julie Lockman, Brunilde Gril, Emily Hua, Diane Palmieri, Joseph W Polli, Stephen Castellino, Stephen D Rubin, Paul R Lockman, Patricia S Steeg, and Quentin R Smith.
• Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, Texas 79106, USA.
• Pharm. Res. 2012 Mar 1; 29 (3): 770-81.

PurposeLapatinib, a small molecule EGFR/HER2 inhibitor, partially inhibits the outgrowth of HER2+ brain metastases in preclinical models and in a subset of CNS lesions in clinical trials of HER2+ breast cancer. We investigated the ability of lapatinib to reach therapeutic concentrations in the CNS following (14)C-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.MethodsDrug concentrations were determined at differing times after administration by quantitative autoradiography and chromatography.Results(14)C-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 h 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 cultured ex vivo from treated brains.ConclusionsResults show that lapatinib distribution to brain metastases of breast cancer is partially restricted and blood-tumor barrier permeability is a key component of lapatinib therapeutic efficacy which varies between tumors.

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