*6.1. Omissions*

In numerous studies, TKIs have been indicated as victims in DDIs while considerably less is known about their role as perpetrators via transporter inhibition [32,60–64]. In this context, it is noteworthy that transporter inhibition studies are not required by regulatory agencies for approval, but rather recommended to evaluate DDI potential [38].

Currently, there are 20 FDA approved TKIs for which the PI does not contain any information on their inhibitory e ffects on OATP1B1 and/or OATP1B3, and this is the case for both agents approved long ago as well as those that were approved more recently. The transport interactions of some of these omitted drugs have been examined by academic investigators as reported in the published literature, and it seems prudent that this information is captured and included in the future in individual PIs and regulatory databases alike. Interestingly, we found that some of the PIs address DDIs that are plausibly attributable to OATPs but this is not always consistently acknowledged due to inconclusive mechanistic insights. For example, dasatinib can dramatically increase plasma levels of the dual OATP1B1 and CYP3A4 substrate, simvastatin, and the individual contribution of each one of these pharmacokinetic components to the DDI is not clearly defined. On the other hand, for many TKIs, no data were found in the published literature on their potential to inhibit OATP1B1 and/or OATP1B3.
