Lapatinib distribution in HER2 overexpressing experimental brain metastases of breast cancer.
OBJECTIVE
Lapatinib, 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.


METHODS
Drug 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.


CONCLUSIONS
Results 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.
Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, Texas 79106, USA.
Kunal S
KS
Taskar
Vinay
V
Rudraraju
Rajendar K
RK
Mittapalli
Ramakrishna
R
Samala
Helen R
HR
Thorsheim
Julie
J
Lockman
Brunilde
B
Gril
Emily
E
Hua
Diane
D
Palmieri
Joseph W
JW
Polli
Stephen
S
Castellino
Stephen D
SD
Rubin
Paul R
PR
Lockman
Patricia S
PS
Steeg
Quentin R
QR
Smith
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D007275:Injections, Intravenous; D000077341:Lapatinib; D051379:Mice; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015854:Up-Regulation
D000970:Antineoplastic Agents; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases