Stephanie van Hoppe

87 ABCB1 restricts brain penetration of the BTK inhibitor ibrutinib while CYP3A limits its oral bioavailability CYP3A4 is of the same order as that seen in human liver [40]. Our data on ibrutinib and ibrutinib-DiOH levels in the CYP3A4 transgenic mouse strains therefore suggest that intestinal CYP3A4 is at least as important as hepatic CYP3A4 in limiting ibrutinib oral bioavailability (Table 2 and Supplemental Table 2), most likely through extensive first- pass metabolism. Altogether, it seems likely that the poor oral bioavailability of ibrutinib is in large part due to its extensive first-pass metabolism, primarily by CYP3A. This may well also apply in humans, which show an absolute ibrutinib oral bioavailability of only ~3-8% [6, 29]. Apart from its impact on oral bioavailability, CYP3A activity does not seem to have a substantial effect on the tissue distribution of ibrutinib and ibrutinib-DiOH. Collectively, our data show that extensive metabolism of ibrutinib by CYP3A in intestine and liver is likely the primary factor in restricting its oral bioavailability, whereas the drug efflux transporters ABCB1 and ABCG2 play very little, if any, role in this process. However, the brain distribution of ibrutinib is clearly limited by ABCB1, whereas the relative distribution of ibrutinib to a range of other tissues is not much affected by either the ABC transporters or CYP3A. Considering that the main types of dose-limiting toxicities of ibrutinib (hemorrhage, opportunistic infections, cytopenia, atrial fibrillation, hypertension) originate outside the CNS, one could consider coadministering ibrutinib with a pharmacological ABCB1 inhibitor in cases where optimal brain penetration of ibrutinib might be therapeutically helpful. However, such treatment modalities would, as always, first have to be very carefully assessed in human patients to judge their practical applicability.