Stephanie van Hoppe

71 ABCB1 restricts brain penetration of the BTK inhibitor ibrutinib while CYP3A limits its oral bioavailability I N T R ODU C T I ON Multidrug efflux transporters of the ATP-binding cassette (ABC) protein family affect the disposition of a wide variety of endogenous and exogenous compounds, including numerous anticancer drugs. ABCB1 (P-glycoprotein) and ABCG2 (BCRP) are expressed in the apical membrane of epithelia in a number of organs that are essential for absorption and elimination of drugs like small intestine, liver, and kidney [1-4]. They are also abundant in luminal membranes of physiological barriers protecting various sanctuary tissues such as the blood-brain (BBB), blood-testis, and blood–placenta barriers. At these barriers, penetrating ABCB1 and ABCG2 substrates are immediately pumped out of the epithelial or endothelial cells back into the blood. As a consequence, only small amounts of drug can accumulate in, for instance, the brain. For anticancer drugs this can compromise treatment of primary brain tumors or (micro-)metastases that are present behind a functionally intact BBB [1-3]. Many anticancer drugs, including tyrosine kinase inhibitors (TKIs), are transported substrates of ABCB1, ABCG2, or both. As a result, these transporters can significantlymodulate the pharmacokinetic behavior, including plasma levels and tissue distribution, and hence the therapeutic efficacy and toxicity profiles of these drugs [5]. Moreover, when functionally expressed in tumor cells themselves, the transporters can directly contribute to multidrug resistance of the malignancy. Ibrutinib (Imbruvica, PCI-32765, Supplemental Figure 1) is an important orally administered TKI currently approved by the FDA and EMA for a number of diseases, including chronic lymphocytic leukemia, small lymphocytic lymphoma, Waldenström’s macroglobulinemia, previously-treated mantle cell lymphoma, relapsed/refractory marginal zone lymphoma and chronic graft versus host disease (cGVHD). The latter application represents the first FDA-approved therapy for this disease [6]. Ibrutinib is an irreversible, covalently binding inhibitor of Bruton’s tyrosine kinase (BTK), with promising clinical activity and tolerability in B-cell malignancies and other diseases. Although ibrutinib was initially developed for treatment of B-cell malignancies, recent publications suggest that ibrutinib could additionally be used for treatment of a range of other malignancies, resulting in an intense interest in this drug [6-9]. Several clinical trials are currently evaluating the efficacy of ibrutinib in metastatic pancreatic adenocarcinoma (NCT02436668), smoldering myeloma (NCT02943473), non-small cell lung cancer with an epidermal growth factor receptor (EGFR) mutation (NCT02321540), and refractory/recurrent primary or secondary central nervous system lymphoma (NCT02315326). A number of these malignancies obviously encompass central nervous system (CNS) lesions, including brain metastases. This broader application spectrum is likely in part due to ibrutinib specifically inhibiting not only BTK, but also a subset of other kinases such as GPIb and GPVI, ErbB4/HER4, Blk, Bmx/Etk, Txk, TEC, EGFR, ErbB2/