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.

Department of Cell Biology and Genetics Faculty of Science Palacky University Slechitelu 11 78371 Olmouc Czech Republic

Department of Clinical Pharmacology and Pharmacoepidemiology University of Heidelberg Im Neuenheimer Feld 410 69120 Heidelberg Germany

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Kim K.B., Saro J., Moschos S.S., Hwu P., Tarhini A.A., Hwu W., Jones G., Wang Y., Rupani H., Kirkwood J.W. A phase I dose finding and biomarker study of TKI258 (dovitinib lactate) in patients with advanced melanoma. J. Clin. Oncol. 2008;26:9026.

André F., Bachelot T., Campone M., Dalenc F., Perez-Garcia J.M., PHurvitz S.A., Turner N., Rugo H., Smith J.W., Deudon S., et al. Targeting FGFR with Dovitinib (TKI258): Preclinical and Clinical Data in Breast Cancer. Clin. Cancer Res. 2013;19:3693–3702. doi: 10.1158/1078-0432.CCR-13-0190. PubMed DOI

Angevin E., Lopez-Martin J.A., Lin C.C., Gschwend J.E., Harzstark A., Castellano D., Soria J.C., Sen P., Chang J., Shi M., et al. Phase I study of dovitinib (TKI258); an oral FGFR; VEGFR; and PDGFR inhibitor; in advanced or metastatic renal cell carcinoma. Clin. Cancer Res. 2013;19:1257–1268. doi: 10.1158/1078-0432.CCR-12-2885. PubMed DOI

Kang Y.K., Yoo C., Ryoo B.Y., Lee J.J., Tan E., Park I., Park J.H., Choi Y.J., Jo J., Ryu J.S., et al. Phase II study of dovitinib in patients with metastatic and/or unresectable gastrointestinal stromal tumours after failure of imatinib and sunitinib. Br. J. Cancer. 2013;109:2309–2315. PubMed PMC

Konecny G.E., Kolarova T., O’Brien N.A., Winterhoff B., Yang G., Qi J., Qi Z., Venkatesan N., Ayala R., Luo T., et al. Activity of the fibroblast growth factor receptor inhibitors dovitinib (TKI258) and NVP-BGJ398 in human endometrial cancer cells. Mol. Cancer Ther. 2013;12:632–642. doi: 10.1158/1535-7163.MCT-12-0999. PubMed DOI

Tai W.T., Cheng A.L., Shiau C.W., Liu C.Y., Ko C.H., Lin M.W., Chen P.J., Chen K.F. Dovitinib induces apoptosis and overcomes sorafenib resistance in hepatocellular carcinoma through SHP-1-mediated inhibition of STAT3. Mol. Cancer Ther. 2012;11:452–463. doi: 10.1158/1535-7163.MCT-11-0412. PubMed DOI

Yoo C., Ryu M.H., Na Y.S., Ryoo B.Y., Park S.R., Kang Y.K. Analysis of serum protein biomarkers, circulating tumor DNA, and dovitinib activity in patients with tyrosine kinase inhibitor-refractory gastrointestinal stromal tumors. Ann. Oncol. 2014;25:2272–7227. PubMed

Galsky M.D., Posner M., Holcombe R.F., Lee K.M., Misiukiewicz K., Tsao C.K., Godbold J., Soto R., Gimpel-Tetra K., Lowe N., et al. Phase Ib study of dovitinib in combination with gemcitabine plus cisplatin or gemcitabine plus carboplatin in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 2014;74:465–471. PubMed PMC

Escudier B., Grünwald V., Ravaud A., Ou Y.C., Castellano D., Lin C.C., Gschwend J.E., Harzstark A., Beall S., Pirotta N., et al. Phase II results of Dovitinib (TKI258) in patients with metastatic renal cell cancer. Clin. Cancer Res. 2014;20:3012–3022. doi: 10.1158/1078-0432.CCR-13-3006. PubMed DOI

Motzer R.J., Porta C., Vogelzang N.J., Sternberg C.N., Szczylik C., Zolnierek J., Kollmannsberger C., Rha S.Y., Bjarnason G.A., Melichar B., et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: An open-label, randomised phase 3 trial. Lancet Oncol. 2014;15:286–296. PubMed PMC

Gottesman M.M., Fojo T., Bates S.E. Multidrug resistance in cancer: Role of ATP-dependent transporters. Nat. Rev. Cancer. 2002;2:48–58. doi: 10.1038/nrc706. PubMed DOI

Wang X., Kay A., Anak O., Angevin E., Escudier B., Zhou W., Feng Y., Dugan M., Schran H. Population pharmacokinetic/pharmacodynamic modeling to assist dosing schedule selection for dovitinib. J. Clin. Pharmacol. 2013;53:14–20. doi: 10.1177/0091270011433330. PubMed DOI

Weiss J., Theile D., Spalwisz A., Burhenne J., Riedel K.D., Haefeli W.E. Influence of sildenafil and tadalafil on the enzyme- and transporter-inducing effects of bosentan and ambrisentan in LS180 cells. Biochem. Pharmacol. 2013;85:265–273. doi: 10.1016/j.bcp.2012.11.020. PubMed DOI

Harmsen S., Koster A.S., Beijnen J.H., Schellens J.H., Meijerman I. Comparison of two immortalized human cell lines to study nuclear receptor-mediated CYP3A4 induction. Drug Metab. Dispos. 2008;36:1166–1171. doi: 10.1124/dmd.107.017335. PubMed DOI

Gupta A., Mugundu G.M., Desai P.B., Thummel K.E., Unadkat J.D. Intestinal human colon adenocarcinoma cell line LS180 is an excellent model to study pregnane X receptor; but not constitutive androstane receptor; mediated CYP3A4 and multidrug resistance transporter 1 induction: Studies with anti-human immunodeficiency virus protease inhibitors. Drug Metab. Dispos. 2008;36:1172–1180. doi: 10.1124/dmd.107.018689. PubMed DOI

Weiss J., Herzog M., Haefeli W.E. Differential modulation of the expression of important drug metabolising enzymes and transporters by endothelin-1 receptor antagonists ambrisentan and bosentan in vitro. Eur. J. Pharmacol. 2011;660:298–304. PubMed

Brandin H., Viitanen E., Myrberg O., Arvidsson A.K. Effects of herbal medicinal products and food supplements on induction of CYP1A2; CYP3A4 and MDR1 in the human colon carcinoma cell line LS180. Phytother. Res. 2007;21:239–244. doi: 10.1002/ptr.2057. PubMed DOI

Yamasaki D., Nakamura T., Okamura N., Kokudai M., Inui N., Takeuchi K., Watanabe H., Hirai M., Okumura K., Sakaeda T. Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. Eur. J. Pharm. Sci. 2009;37:126–132. doi: 10.1016/j.ejps.2009.01.009. PubMed DOI

Li W., Harper P.A., Tang B.K., Okey A.B. Regulation of cytochrome P450 enzymes by aryl hydrocarbon receptor in human cells: CYP1A2 expression in the LS180 colon carcinoma cell line after treatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin or 3-methylcholanthrene. Biochem. Pharmacol. 1998;56:599–612. doi: 10.1016/S0006-2952(98)00208-1. PubMed DOI

Harper P.A., Prokipcak R.D., Bush L.E., Golas C.L., Okey A.B. Detection and characterization of the Ah receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin in the human colon adenocarcinoma cell line LS180. Arch. Biochem. Biophys. 1991;290:27–36. doi: 10.1016/0003-9861(91)90587-9. PubMed DOI

Schinkel A.H., Wagenaar E., van Deemter L., Mol C.A., Borst P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Investig. 1995;96:1698–1705. doi: 10.1172/JCI118214. PubMed DOI PMC

Pavek P., Merino G., Wagenaar E., Bolscher E., Novotna M., Jonker J.W., Schinkel A.H. Human breast cancer resistance protein: Interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J. Pharmacol. Exp. Ther. 2005;312:144–152. doi: 10.1124/jpet.104.073916. PubMed DOI

Schinkel A.H., Wagenaar E., Mol C.A., van Deemter L. P-Glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Investig. 1996;97:2517–2524. doi: 10.1172/JCI118699. PubMed DOI PMC

König J., Cui Y., Nies A.T., Keppler D. Localization and genomic organization of a new hepatocellular organic anion transporting polypeptide. J. Biol. Chem. 2000;275:23161–23168. doi: 10.1074/jbc.M001448200. PubMed DOI

Köni J., Cui Y., Nies A.T., Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am. J. Physiol. Gastrointest. Liver Physiol. 2000;278:G156–G164. PubMed

Novotna A., Pavek P., Dvorak Z. Novel stably transfected gene reporter human hepatoma cell line for assessment of aryl hydrocarbon receptor transcriptional activity: Construction and characterization. Environ. Sci. Technol. 2011;45:10133–10139. doi: 10.1021/es2029334. PubMed DOI

Holló Z., Homolya L., Hegedüs T., Sarkadi B. Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. FEBS Lett. 1996;383:99–104. doi: 10.1016/0014-5793(96)00237-2. PubMed DOI

Weiss J., Dormann S.M., Martin-Facklam M., Kerpen C.J., Ketabi-Kiyanvash N., Haefeli W.E. Inhibition of P-glycoprotein by newer antidepressants. J. Pharmacol. Exp. Ther. 2003;305:197–204. doi: 10.1124/jpet.102.046532. PubMed DOI

Weiss J., Haefeli W.E. Evaluation of inhibitory potencies for compounds inhibiting P-glycoprotein but without maximum effects: f2 values. Drug Metab. Dispos. 2006;34:203–207. doi: 10.1124/dmd.105.007377. PubMed DOI

Weiss J., Rose J., Storch C.H., Ketabi-Kiyanvash N., Sauer A., Haefeli W.E., Efferth T. Modulation of human BCRP (ABCG2) activity by anti-HIV drugs. J. Antimicrob. Chemother. 2007;59:238–245. doi: 10.1093/jac/dkl474. PubMed DOI

Peters T., Lindenmaier H., Haefeli W.E., Weiss J. Interaction of the mitotic kinesin Eg5 inhibitor monastrol with P-glycoprotein. Naunyn Schmiedebergs Arch. Pharmacol. 2006;372:291–299. doi: 10.1007/s00210-005-0022-5. PubMed DOI

Albermann N., Schmitz-Winnenthal F.H., Z’graggen K., Volk C., Hoffmann M.M., Haefeli W.E., Weiss J. Expression of the drug transporters MDR1/ABCB1; MRP1/ABCC1; MRP2/ABCC2; BCRP/ABCG2; and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver. Biochem. Pharmacol. 2005;70:949–958. doi: 10.1016/j.bcp.2005.06.018. PubMed DOI

König S.J., Herzog M., Theile D., Zembruski N., Haefeli W.E., Weiss J. Impact of drug transporters for the cellular resistance towards saquinavir and darunavir. J. Antimicrob. Chemother. 2010;65:2319–2328. doi: 10.1093/jac/dkq324. PubMed DOI

Dvorak Z., Vrzal R., Henklova P., Jancova P., Anzenbacherova E., Maurel P., Svecova L., Pavek P., Ehrmann J., Havlik R., et al. JNK inhibitor SP600125 is a partial agonist of human aryl hydrocarbon receptor and induces CYP1A1 and CYP1A2 genes in primary human hepatocytes. Biochem. Pharmacol. 2008;5:580–588. doi: 10.1016/j.bcp.2007.09.013. PubMed DOI

Ayed-Boussema I., Pascussi J.M., Maurel P., Bacha H., Hassen W. Zearalenone activates pregnane X receptor; constitutive androstane receptor and aryl hydrocarbon receptor and corresponding phase I target genes mRNA in primary cultures of human hepatocytes. Environ. Toxicol. Pharmacol. 2011;31:79–87. doi: 10.1016/j.etap.2010.09.008. PubMed DOI

Vandesompele J., de Preter K., Pattyn F., Poppe B., van Roy N., de Paepe A., Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3 doi: 10.1186/gb-2002-3-7-research0034. PubMed DOI PMC

Weiss J., Sauer A., Divac N., Herzog M., Schwedhelm E., Böger R.H., Haefeli W.E., Benndorf R.A. Interaction of angiotensin receptor type 1 blockers with ATP-binding cassette transporters. Biopharm. Drug Dispos. 2010;31:150–161. doi: 10.1002/bdd.699. PubMed DOI

Mandery K., Glaeser H., Fromm M.F. Interaction of innovative small molecule drugs used for cancer therapy with drug transporters. Br. J. Pharmacol. 2012;165:345–362. doi: 10.1111/j.1476-5381.2011.01618.x. PubMed DOI PMC

Sarker D., Molife R., Evans T.R., Hardie M., Marriott C., Butzberger-Zimmerli P., Morrison R., Fox J.A., Heise C., Louie S., et al. A phase I pharmacokinetic and pharmacodynamic study of TKI258; an oral; multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin. Cancer Res. 2008;14:2075–2081. doi: 10.1158/1078-0432.CCR-07-1466. PubMed DOI

Kim K.B., Chesney J., Robinson D., Gardner H., Shi M.M., Kirkwood J.M. Phase I/II and pharmacodynamic study of dovitinib (TKI258); an inhibitor of fibroblast growth factor receptors and VEGF receptors; in patients with advanced melanoma. Clin. Cancer Res. 2011;17:7451–7461. doi: 10.1158/1078-0432.CCR-11-1747. PubMed DOI

Xiao Z., Ding N., Xiao G., Wang S., Wu Y., Tang L. Reversal of multidrug resistance by gefitinib via RAF1/ERK pathway in pancreatic cancer cell line. Anat. Rec. 2012;295:2122–2128. doi: 10.1002/ar.22552. PubMed DOI

Garcia R., Franklin R.A., McCubrey J.A. EGF induces cell motility and multi-drug resistance gene expression in breast cancer cells. Cell Cycle. 2006;5:2820–2826. doi: 10.4161/cc.5.23.3535. PubMed DOI

McCubrey J.A., Steelman L.S., Abrams S.L., Lee J.T., Chang F., Bertrand F.E., Navolanic P.M., Terrian D.M., Franklin R.A., D’Assoro A.B., et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv. Enzyme Regul. 2006;46:249–279. doi: 10.1016/j.advenzreg.2006.01.004. PubMed DOI

Yang H.Y., Zhao L., Yang Z., Zhao Q., Qiang L., Ha J., Li Z.Y., You Q.D., Guo Q.L. Oroxylin A reverses multi-drug resistance of human hepatoma BEL7402/5-FU cells via downregulation of P-glycoprotein expression by inhibiting NF-κB signaling pathway. Mol. Carcinog. 2012;51:185–195. doi: 10.1002/mc.20789. PubMed DOI

Yueh M.F., Mellon P.L., Tukey R.H. Inhibition of human UGT2B7 gene expression in transgenic mice by the constitutive androstane receptor. Mol. Pharmacol. 2011;79:1053–1060. doi: 10.1124/mol.110.070649. PubMed DOI PMC

Harmsen S., Meijerman I., Maas-Bakker R.F., Beijnen J.H., Schellens J.H. PXR-mediated P-glycoprotein induction by small molecule tyrosine kinase inhibitors. Eur. J. Pharm. Sci. 2013;48:644–649. doi: 10.1016/j.ejps.2012.12.019. PubMed DOI

Ebert B., Seidel A., Lampen A. Identification of BCRP as transporter of benzo(a)pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists. Carcinogenesis. 2005;26:1754–1763. doi: 10.1093/carcin/bgi139. PubMed DOI

Zhang L., Zhang Y.D., Strong J.M., Reynolds K.S., Huang S.M. A regulatory viewpoint on transporter-based drug interactions. Xenobiotica. 2008;38:709–724. doi: 10.1080/00498250802017715. PubMed DOI

Pfrunder A., Gutmann H., Beglinger C., Drewe J. Gene expression of CYP3A4; ABC-transporters (MDR1 and MRP1-MRP5) and hPXR in three different human colon carcinoma cell lines. J. Pharm. Pharmacol. 2003;55:59–66. doi: 10.1111/j.2042-7158.2003.tb02434.x. PubMed DOI

Kliewer S.A., Goodwin B., Willson T.M. The nuclear pregnane X receptor: A key regulator of xenobiotic metabolism. Endocr. Rev. 2002;23:687–702. doi: 10.1210/er.2001-0038. PubMed DOI

Urquhart B.L., Tirona R.G., Kim R.B. Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: Implications for interindividual variability in response to drugs. J. Clin. Pharmacol. 2007;47:566–578. doi: 10.1177/0091270007299930. PubMed DOI

Jigorel E., Le Vee M., Boursier-Neyret C., Parmentier Y., Fardel O. Differential regulation of sinusoidal and canalicular hepatic drug transporter expression by xenobiotics activating drug-sensing receptors in primary human hepatocytes. Drug Metab. Dispos. 2006;34:1756–1763. doi: 10.1124/dmd.106.010033. PubMed DOI

Teng S., Jekerle V., Piquette-Miller M. Induction of ABCC3 (MRP3) by pregnane X receptor activators. Drug Metab. Dispos. 2003;31:1296–1299. doi: 10.1124/dmd.31.11.1296. PubMed DOI

Kast H.R., Goodwin B., Tarr P.T., Jones S.A., Anisfeld A.M., Stoltz C.M., Tontonoz P., Kliewer S., Willson T.M., Edwards P.A. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor; farnesoid X-activated receptor; and constitutive androstane receptor. J. Biol. Chem. 2002;277:2908–2915. doi: 10.1074/jbc.M109326200. PubMed DOI

Geick A., Eichelbaum M., Burk O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 2001;276:14581–14587. doi: 10.1074/jbc.M010173200. PubMed DOI

Hariparsad N., Nallani S.C., Sane R.S., Buckley D.J., Buckley A.R., Desai P.B. Induction of CYP3A4 by efavirenz in primary human hepatocytes: Comparison with rifampin and phenobarbital. J. Clin. Pharmacol. 2004;44:1273–1281. doi: 10.1177/0091270004269142. PubMed DOI