Abstract 5218: Breast Cancer Resistance Protein (ABCG2) and P-glycoprotein (ABCB1) Transport Ibrutinib and May Restrict Its Oral Availability and Brain Accumulation, Whereas CYP3A4 Limits Ibrutinib Oral Availability

Abstract Introduction: Ibrutinib (Imbruvica, PCI-32765) is an orally administered tyrosine kinase inhibitor (TKI) approved by the FDA in 2014 for treatment of B-cell malignancies. Ibrutinib is a confirmed irreversible inhibitor of Bruton tyrosine kinase (BTK) with promising clinical activity and tolerability in B-cell malignancies. Ibrutinib is converted into several metabolites, primarily by CYP3A4. Its main metabolite, PCI45227, has an inhibitory activity towards BTK approximately 10 times lower than its parent compound. We investigated whether ibrutinib is a substrate for the multidrug efflux transporters ABCG2 and ABCB1 and whether these transporters influence oral availability and brain and other tissue accumulation of ibrutinib. Materials: We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of ibrutinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral ibrutinib disposition, we used appropriate knockout mouse strains. To assess the role of Cyp3a in the bioavailability of ibrutinib we used knockout strains as well as humanized CYP3A4 strains and measured the ibrutinib and PCI45227 concentrations at various time points. Results: Ibrutinib was transported reasonably well by hABCB1 and mAbcg2, but not by hABCG2 in vitro. Upon oral administration of ibrutinib, Cyp3a-/-, Abcg2-/-, Abcb1a1b-/-, and Abcg2;Abcb1a1b-/- mice displayed an increase of 9.8-, 1.3-, 1.6- and 1.1 fold in ibrutinib plasma AUC0-20min compared to wild-type mice. At 20 min, preliminary data indicated that the relative brain accumulation of ibrutinib was not significantly altered for the Abcg2;Abcb1a/1b-/- mice compared to wild-type mice. Conclusion: Abcg2 and Abcb1a/1b possibly restrict oral availability of ibrutinib. Based on our (preliminary) data ibrutinib may not substantially cross the blood-brain barrier. Cyp3a restricts the oral availability of ibrutinib and therefore inhibition of this enzyme may be of clinical importance for patients undergoing ibrutinib therapy. Citation Format: Stephanie van Hoppe, Gert-Jan Rood, Els Wagenaar, Rolf Sparidans, Jos Beijnen, Alfred Schinkel. Breast cancer resistance protein (ABCG2) and P-glycoprotein (ABCB1) transport ibrutinib and may restrict its oral availability and brain accumulation, whereas CYP3A4 limits ibrutinib oral availability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5218. doi:10.1158/1538-7445.AM2017-5218