Stephanie van Hoppe

35 ABCG2 & ABCB1 transport afatinib and restrict its oral availability and brain accumulation Based on our findings, it is likely that tumors expressing ABCB1 and/or ABCG2 will also demonstrate resistance to afatinib-based chemotherapy. Inhibiting these transporters during afatinib therapy might therefore be beneficial for the response of these tumors. It may further be possible to increase afatinib levels in the brain of patients with CNS involvement for better treatment efficacy when afatinib is coadministered with an efficacious dual inhibitor of ABCB1 and ABCG2 such as elacridar. From our study it appears that this sort of coadministration might perhaps also increase the oral availability and consequently overall tissue levels of afatinib, which should be taken into account for possible dose adjustment, to avoid increased toxicity. CON C LU S I ON Our study shows that ABCG2 and ABCB1 by themselves and together markedly restrict oral availability and brain disposition of afatinib, and mediate its elimination. These results indicate that coadministration of efficacious ABCG2 and ABCB1 inhibitors may increase exposureof afatinib inpatients, in transporter-expressing tumors, but especially also in the brain, thus providing an option to better treat NSCLC and its metastases positioned in part or in whole behind a functionally intact blood-brain barrier. AC KNOWL E DG EME N T S We gratefully acknowledge the technical assistance of Levi Buil during the experimental phase, and Cristina Lebre, Changpei Gan, Diana Martinez, Jing Wang, Xiaozhe Qi and Yaogeng Wang for critical reading of this manuscript.