**7. Conclusions**

The development and use of TKIs as molecular targeted therapies for the treatment of a diverse array of malignant diseases continues to rapidly increase, and 50 of such agents have now been approved for human use. However, polypharmacy regimens commonly applied in oncology with these TKIs creates a high risk for the occurrence of clinically-relevant DDIs. Although the extent to which such DDIs are influenced by the ability of many TKIs to impact the function of transporter-mediated uptake mechanisms in hepatocytes remains relatively poorly studied, data have accumulated in recent years highlighting that TKIs can act as perpetrators in DDIs by inhibiting OATP1B1 and/or OATP1B3. Many of these recent observations have been made with the use of transfected cell-based in vitro models, and a summary of this available evidence has identified substantial methodological differences between various studies and has highlighted several important limitations in the chosen approaches that have generated incongruent reports. Given that these in vitro studies are the most frequently employed nonclinical tool in aiding decision making for patient care, it is pertinent that regulatory guidance documents and available published literature provide consistent and corresponding results. To further improve consistency in the outcome of transporter-mediated DDI studies involving TKIs, specific recommendations are offered that may assist investigators in the design of future studies in order to provide unequivocal data pertaining to the inhibitory potential of both established as well as investigational TKIs that could be rationally used to further refine the predictive ability of DDIs and ultimately optimize the outcome of treatment in patients with cancer.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/12/9/856/s1, Table S1: Prescribing Information, Table S2. FDA guidance for TKI interactions with OATP1B1 and OATP1B3, Table S3. EMA guidance for TKI interactions with OATP1B1 and OATP1B3, Table S4. Comparison of PI, FDA, and EMA regulatory documents, Table S5. In vitro studies for TKIs as perpetrators in OATP-mediated DDIs, Table S6. In vivo studies for TKIs as perpetrators in OATP-mediated DDIs Table S7. Literature on clinical studies focused on TKIs in potential DDIs Table S8. Comparison of the PI, FDA, and EMA guidance documents to the literature for OATP1B1 inhibition and OATP1B3 inhibition, Table S9. TKIs for which no relevant literature was found for OATP-mediated inhibition by TKIs.

**Author Contributions:** Each of the authors have read and approved this version of the manuscript and agrees to be held accountable for the accuracy and integrity of all included content. Each named author has substantially contributed to conducting the underlying research and drafting this manuscript. Individual contributions are illustrated in the following statements: Conceptualization, D.A.G., Z.T., A.S. and S.D.B.; methodology, D.A.G., Z.T. and E.D.E.; investigation, D.A.G., Z.T. and E.D.E.; interpretation of data, D.A.G. and Z.T.; writing—Original draft preparation, D.A.G. and Z.T.; writing—Review and editing, D.A.G., Z.T., E.D.E., A.S. and S.D.B.; supervision, A.S. and S.D.B.; funding acquisition, E.D.E., A.S. and S.D.B. All authors have read and agreed to the published version of the manuscript.

**Funding:** The work was supported in part by the National Institutes of Health (Grants R01CA215802 (to A.S.) and R01CA138744 (to S.D.B.)), by the OSU Comprehensive Cancer Center Pelotonia foundation (A.S. and S.D.B.) and by the Pelotonia Fellowship Program (E.D.E.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

**Conflicts of Interest:** The authors declare no conflict of interest
