TAK-285, a Novel HER2/EGFR Inhibitor, Penetrates the CNS in Rats with an Intact Blood Brain Barrier (BBB).
Authors: J. Wu, M. Liao, J. Gordon, Q. Zhu, S. Yu, A. Bulychev, C. Xia
Journal: Cancer Research (2009)

Abstract Background: Approximately one third of patients with HER2-overexpressing (HER2+) metastatic breast cancer develop brain metastases. Treatment options for patients whose brain metastases have progressed after radiotherapy are urgently needed. The currently approved HER2-targeted therapies, trastuzumab and lapatinib, have generally shown limited activity against brain metastases, likely due to the limited brain penetration of these drugs. Brain penetration is mediated by multiple factors including drug permeability, tissue binding, and the expression of efflux transporters (P-gp and BCRP) and their interactions with the drug. TAK-285 is a novel, orally active, dual HER2/EGFR inhibitor currently under clinical development. In this nonclinical work, we evaluated the permeability, interactions with efflux transporters, and brain penetration of TAK-285, along with lapatinib and neratinib, using in vitro and animal models.Material and Methods: The first study evaluated the permeability of TAK-285, lapatinib, and neratinib and their interactions with efflux transporters using the Caco-2 cell monolayer system in the absence or presence of efflux pump inhibitors. The second study evaluated brain penetration of TAK-285, lapatinib and neratinib after a single oral administration in rats with an intact BBB.Results: In the Caco-2 cell model, TAK-285 showed high permeability with an efflux ratio of 1.7, indicating it is not a substrate for efflux pumps. The efflux pump inhibitors LY335979 (an inhibitor of P-gp), Ko143 (an inhibitor of BCRP), and GF120918 (an inhibitor of BCRP and P-gp) had no marked effect on the efflux ratio of TAK-285, further confirming that TAK-285 is not a substrate for P-gp and BCRP. Lapatinib and neratinib showed low to medium permeability and appeared to be substrates for P-gp/BCRP in this testing system. In the rat brain penetration study, the brain-to-plasma AUC ratio for total (free and bound) TAK-285, lapatinib, and neratinib was 0.202, 0.0243, and 0.0263, respectively.Discussion: These nonclinical studies showed that, unlike lapatinib and neratinib, TAK-285 is not a substrate for the efflux transporters, P-gp and BCRP. Based on published information, all of the approved receptor tyrosine kinase inhibitors are substrates for efflux transporters. Additionally, in rats with an intact BBB, the brain-to-plasma AUC ratio for TAK-285 was substantially higher than that of lapatinib and neratinib. The AUC ratios observed in this study for lapatinib and neratinib are similar to the proportion of blood volume in the rat brain (ie, outside the CNS) relative to the total rat brain volume. This suggests the actual brain-to-plasma AUC ratio for TAK-285 in rats may be much greater than 8-fold of that of lapatinib and neratinib calculated based on these measured AUC ratios. Consequently, TAK-285 may have a unique role in the treatment of brain lesions in patients with HER2- or EGFR-dependent tumors. Furthermore, TAK-285 may not be subject to drug resistance conferred by efflux transporters. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5098.