**10. Drug-drug interaction with TKI**

DDIs represent a serious concern, especially for agents that influenced by efflux transporters and CYP3A4 enzyme, and can produce clinically relevant drug interactions by alteration of its bioavailability. Because the majority of TKIs are substrate of CYP3A4 and/or P-gp, DDI with CYP3A4 and/or P-gp inhibitors and inducers must be taken into account, and they must be used with caution, as advised in the package insert. Recently, it has been reported that coprescription of those medicines, which may induce or inhibit the metabolic pathways used by TKIs, is very high. Overall coprescribing rates of drugs that induce metabolism of TKI and may lead to decrease the effectiveness of TKIs ranged from 23 to 57%, whereas coprescribing rates of drugs that inhibit metabolism of TKIs and may increase its toxicity ranged from 24 to 74% [122]. For example, coadministration of imatinib with dual inhibitors CYP3A4 and P-gp increases not only the plasma concentration but also the intracellular concentration of imatinib. Dual inhibitors CYP3A4 and P-gp, such as verapamil fluconazole, itraconazole [123], erythromycin, clarithromycin [124], cyclosporine [125], and ketoconazole [126], increased the intracellular concentration of imatinib by inhibiting both its CYP3A4-mediated metabolism and its efflux through P-gp, which might result in increasing its cellular toxicity. Moreover, P-gp-mediated efflux inhibition by proton pump inhibitors, such as pantoprazole, has reported to increase the brain concentration of imatinib [127]. In contrast, coadministration of CYP3A4 inducers, such as rifampicin or certain antiepileptics, may lead to a reduction in imatinib exposure of up to 74% [24, 110]. Similarly, inhibitors of both CYP3A4 and P-gp increase both the plasma and intracellular concentrations of dasatinib as well, which are also expected to occur for verapamil, erythromycin, clarithromycin, fluconazole, itraconazole [123], cyclosporine [125], and ketoconazole [123, 128]. Concomitant administration of the CYP3A4 inducer rifampicin leads to a reduction in dasatinib exposure of 80% [24, 129, 130]. The area under curve (AUC) of nilotinib is increased 3-fold in healthy subjects receiving ketoconazole [130], whereas coadministration of CYP3A4 inducers, such as rifampicin, leads to a 4.8-fold reduction in nilotinib exposure [24, 129, 130]. Administration of gefitinib in the presence of rifampicin reduces the AUC of gefitinib by 83%, while in the presence of itraconazole, the AUC of gefitinib is increased by 78% [24, 131]. Furthermore, coadministration of ketoconazole results in a 3.6-fold increase in lapatinib plasma exposure, whereas coadministration of carbamazepine results in a decrease in the AUC of lapatinib by 72% [24, 132]. Although the result of above studies confirmed the risk of frequent DDIs among TKIs, but did not addressed the clinical consequences of these, that is, increased toxicity or therapeutic failure. Moreover, in some cases, in spite of knowing, these potential interacting combinations could have been intentionally prescribed by physicians because they considered the potential benefits to outweigh the risks or because the patient had the ability to tolerate these combinations in the past [133]. Since most of these TKIs are relatively new, their scientific evidence that supports their DDIs is limited. Therefore, it is not unexpected to observe that medical oncologists are not able to report TKI DDI pairs, which might have a high probability of causing deleterious effects in the treatment of cancer patients [134].
