Stephanie van Hoppe

116 Chapter 5 levels, and a decrease in DMP levels [27]. The latter effect might indicate that in patients there are no efficient alternative pathways to form DMP from ponatinib, illustrating a difference between mice and man. Nonetheless, all data suggest that altered activity of CYP3A, which commonly occurs in humans, may affect the effective exposure of the body to ponatinib, and thus its therapeutic efficacy and toxicity risks. Ponatinib is approved for treatment for CML and ALL. However, its use has to be carefullymonitored, with revised prescribing information including a black box warning, and the need for risk evaluation and mitigation strategies mainly because of serious cardiovascular risks [50], vascular occlusions and heart failure, but also hepatotoxicity. Ponatinib use therefore remains limited to second-generation drug-resistant and (T351I) mutated patients with Ph+ ALL [51], or as third-line therapy in CML [52]. Since our data indicate that ABC efflux transporters and CYP3A4 could affect the biological availability of ponatinib and its active metabolite DMP at several levels, it will be important to also consider these factors as possible players in unexpected toxicity of ponatinib. Based on our findings, it is likely that tumors substantially expressing ABCB1 and/or ABCG2 will demonstrate resistance to ponatinib. Thus, inhibiting these transporters with effective dual ABCG2 and ABCB1 inhibitors such as elacridar during ponatinib therapy could potentially improve the tumor response. It may further be possible to increase the ponatinib concentration in the brain of patients with CNS tumors or metastases when ponatinib is coadministered with elacridar. Indeed, a recent case study suggested that ponatinib does not normally effectively enter the CNS [53]. Our results suggest that the oral availability, and hence the risk of toxicity, of ponatinib is not likely to be increased by such an elacridar coadministration treatment. In contrast, the oral availability of ponatinib could potentially be enhanced by coadministration of a CYP3A4 inhibitor, such as ketoconazole. However, caution should be exercised to prevent unexpected toxicity. Collectively, our findings suggest that co-administration of a dual inhibitor of ABCB1 and ABCG2 may increase the exposure to ponatinib and its active metabolite for brain (micro)metastases positioned behind a functionally intact blood-brain barrier, and could thus reduce the chance that patients will ultimately die of such normally poorly tractable lesions.