Dovitinib (TKI-258) is under development for the treatment of diverse
cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important
drug metabolising
enzymes and
drug transporters and its efficacy in multidrug resistant cells in vitro.
P-glycoprotein (P-gp, MDR1, ABCB1) inhibition was evaluated by
calcein assay, inhibition of
breast cancer resistance
protein (BCRP, ABCG2) by
pheophorbide A efflux, and inhibition of organic
anion transporting
polypeptides (OATPs) by 8-fluorescein-cAMP uptake. Inhibition of
cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and
enzymes was quantified by real-time RT-PCR. Possible
aryl hydrocarbon receptor (AhR) activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP.
Dovitinib weakly inhibited
CYP2C19,
CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 μM). Among the genes investigated,
dovitinib only induced
mRNA expression of
CYP1A1,
CYP1A2, ABCC3 (coding for
multidrug resistance-associated protein 3), and ABCG2 and suppressed
mRNA expression of some transporters and
drug metabolising
enzymes. AhR reporter gene assay demonstrated that
dovitinib is an activator of this
nuclear receptor.
Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that
dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that
dovitinib might act as a perpetrator
drug in pharmacokinetic
drug-drug interactions.