We further performed a proteinase susceptibility test out purified mitochondria proteins Tim23

It is known that some substrates, including other tyrosine kinase inhibitors, stimulate ATPase activity of ABCB1 and ABCG2 at lower concentrations, but inhibit ATPase activity at higher concentrations. Taken together, the data in Figure 2 suggest that quizartinib may be transported by both ABCB1 and ABCG2 at lower concentrations. However, this conclusion needs to be validated by measuring the net efflux of quizartinib from polarized cells such as LLC-PK1 or MDCK expressing ABCB1 or ABCG2. This will help further in understanding the role of these transporters in altering quizartinib sensitivity or bioavailability. Quizartinib was found to exhibit collateral sensitivity in K562/ ABCB1 and K562/ABCG2 cells, in relation to parental K562 cells. Collateral sensitivity is an incompletely understood phenomenon, for which four possible mechanisms have been proposed: 1) production of reactive oxygen species via futile hydrolysis of ATP, 2) exploitation of energetic sensitivities, 3) extrusion of endogenous substrates that are essential for cell survival, or 4) perturbation of the plasma membrane. The first and third of these mechanisms require Proxyfan oxalate direct interaction with the ABC protein, as appears to be the case for quizartinib with ABCB1 and ABCG2. Chemotherapeutic agents that are used to treat AML and that are ABCG2 substrates include mitoxantrone, topotecan, flavopiridol and the nucleoside analogs cladribine, clofarabine and fludarabine. All of these drugs are currently in use or under investigation in diverse therapeutic regimens in AML. Based on our data presented here, co-administration of quizartinib has the potential to chemosensitize AML cells to any of these drugs, and thus the potential to enhance their efficacy and/ or allow their administration at lower doses, thereby decreasing toxicity. A significant correlation was recently reported between presence of FLT3-ITD and ABCG2 overexpression in pretreatment AML cells. Moreover, DFS was significantly shorter in patients with both FLT3-ITD and ABCG2 overexpression. Of note, patients in this series were treated with a fludarabine-based chemotherapy regimen, and fludarabine is an ABCG2 substrate. Co-administration of quizartnib with chemotherapy and, particularly, with ABCG2 substrate chemotherapy drugs, has the potential to overcome the negative impact of both FLT3-ITD and ABCG2 overexpression. The dose-limiting toxicity of quizartinib is QT prolongation, and it may be exacerbated by co-administration of other drugs that prolong the QT interval. These include, among others, fluoroquinolone antibiotics, phenothiazine antiemetics, methadone, and the antiarrhythmic agents quinidine, procainamide, sotalol, amiodarone and verapamil. The fluoroquinolone antibiotics, with those in current use including ciprofloxacin, levofloxacin and moxifloxacin, are drugs that are commonly administered to AML patients and may therefore be commonly co-administered with quizartinib. The fluoroquinilones are ABCG2 substrates, and their intestinal absorption and pharmacokinetic profile may therefore be altered when they are co-administered with quizartinib. Indeed we demonstrated that quizartinib increased accumulation of ciprofloxacin in a concentration- dependent manner in cells overexpressing ABCG2. An additional potential consequence of ABCG2 inhibition in patients with AML is impact on the risk of hyperuricemia and gout. ABCG2 has been found to be a urate efflux transporter, with increased incidence of both hyperuricemia and gout in association with the Q141K ABCG2 single nucleoside polymorphism, which results in decreased urate transport. It is therefore logical to infer that inhibition of ABCG2 function by agents such as quizartinib has the potential to increase uric acid levels, which should be mitigated by co-administration of a urate-lowering agent. Finally, while clinically targeted plasma levels of quizartinib are below those needed for inhibition of ABCB1-mediated transport of chemotherapy drugs in AML cells, levels in the gastrointestinal tract are likely to be sufficient to inhibit ABCB1-mediated intestinal drug transport and thus increase absorption of coadministered ABCB1 substrate drugs, including those that have the potential to prolong the QT interval. We have shown that the second-generation bis-aryl urea FLT3 inhibitor quizartinib is a potent inhibitor of drug transport by ABCG2 at clinically targeted concentrations and thus may sensitize AML cells expressing ABCG2 to ABCG2 substrate chemotherapy drugs. It may have particular impact in the prognostically unfavorable subset of patients whose AML cells exhibit both FLT3-ITD and ABCG2 overexpression. Quizartinib also likely increases intestinal uptake and alters the pharmacokinetic profile of orally co-administered ABCG2 substrate drugs, including those that prolong the QT interval, such as fluoroquinolone antibiotics. Quizartinib inhibits drug transport by ABCB1 at higher concentrations, and is unlikely to chemosensitize, but likely increases intestinal uptake of orally co-administered ABCB1 substrate drugs, which include agents that prolong the QT interval. These interactions should be considered in the design of combination regimens incorporating quizartinib and chemotherapeutic agents and in choice of concomitant medications to be administered with quizartinib.

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