Stephanie van Hoppe

15 Introduction models as well as humanized transgenic mouse models in order to unravel interactions between the ABC transporters, CYP enzymes and many drugs. In this thesis we made use of previously generated single and combination knockout mouse models of the ABCB1 and ABCG2 transporters as well as the Cyp3a knockout mouse model along with the humanized transgenic CYP3A4 mouse models to study their interactions with the tyrosine kinase inhibitors afatinib, osimertinib, ibrutinib and ponatinib. For all of these drugs we found that they are transported to a greater or lesser extent by ABCB1 and/or ABCG2. In the mouse models this transport sometimes modestly restricted the oral availability, but it always resulted in pronounced decreases in brain penetration of the drugs. Implications of the latter findings are that brain tumors or (micro)metastases that are positioned behind a functional blood-brain barrier may not be readily accessible to these drugs, and therefore respond very poorly to the therapy. The same might apply to tumors that themselves substantially express one or both of these transporters. For this reason it may be considered to try and combine therapy with these TKIs with coadministration of efficient ABCB1 and/or ABCG2 inhibitors, such as elacridar in mice. In the past we and other groups have shown that this principle works well in improving brain penetration of substrate drugs in preclinical (mouse) studies. However, mouse models should not be used in a simplistic one-to-one way to predict what is going to happen in humans. Ultimately, this can only be done in trials in humans, optimally designed with a basic understanding of the underlying principles in mind. Many of the targeted anticancer drugs that we (and various other groups) have tested so far are strongly affected by both ABC transporters, albeit to variable relative extents (21, 22). From this perspective, perhaps the use of primarily ABCB1 inhibitors in the past instead of highly effective dual inhibitors of both ABCB1 and ABCG2 may also have contributed to failure of some clinical inhibitor trials. However, the real-life clinical treatment of tumors is complicated, and there can be many additional reasons why application of ABCB1 inhibitors has so far failed to substantially improve therapy response. WHAT N E X T ? Improving brain accumulation of drugs is of high interest in the clinic due to the fact that current therapies are often inefficient in eradicating brain tumors or brain metastases situated in whole or in part behind an intact blood-brain barrier (BBB) (9, 10). However, it appears to be a challenge for pharmaceutical companies to develop drugs that are not transported by these ABC transporters. The promise of improved brain penetration for scores of drugs using potent 3rd generation ABCB1 and/or ABCG2 inhibitors has