Sunitinib is a tyrosine kinase inhibitor indicated for the treatment of gastrointestinal stromal tumor, advanced renal cell carcinoma, and pancreatic neuroendocrine tumors. The aim of this article is to describe the pharmacological interactions between sunitinib and commonly prescribed drugs.
Method
We reviewed available information on pharmacological interactions between sunitinib and concomitantly prescribed drugs. Drugs were grouped into different therapeutic groups according to the Anatomical Therapeutic Chemical (ATC) classification.
Results
Sunitinib interacts with CYP3A4 inducers or inhibitors and with P-glycoprotein and ABCG2 substrates. Pharmacodynamic interactions with drugs have also been found.
Conclusion
Current information on drug interactions between sunitinib and other drugs is scarce and most of the times it is difficult to apply to clinical practice. Even so, this difficulty in managing drug interactions should not be a reason to ignore them as they can help to explain intolerances and treatment failures.
BannaGLCollovàEGebbiaV. Anticancer oral therapy: Emerging related issues. Cancer Treat Rev2010; 36(8): 595–605.
2.
Di GionPKanefendtFLindauerA. Clinical pharmacokinetics of tyrosine kinase inhibitors: Focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet2011; 50(9): 551–603.
3.
Van ErpNPGelderblomHGuchelaarH-J. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev2009; 35(8): 692–706.
HoukBEBelloCLPolandB. Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: Results of a pharmacokinetic/pharmacodynamic meta-analysis. Cancer Chemother Pharmacol2010; 66(2): 357–371.
6.
BlowerPDe WitRGoodinS. Drug-drug interactions in oncology: Why are they important and can they be minimized?Crit Rev Oncol Hematol2005; 55(2): 117–142.
7.
PajaresBTorresETrigoJM. Tyrosine kinase inhibitors and drug interactions: A review with practical recommendations. Clin Transl Oncol2012; 14(2): 94–101.
8.
AdamsVRLeggasM. Sunitinib malate for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors. Clin Ther2007; 29(7): 1338–1353.
9.
KroissMQuinklerMLutzWK. Drug interactions with mitotane by induction of CYP3A4 metabolism in the clinical management of adrenocortical carcinoma. Clin Endocrinol2011; 75(5): 585–591.
10.
SzałekEKarbownikAPołomW. Sunitinib in combination with clarithromycin or azithromycin – Is there a risk of interaction or not?Pharmacol Rep2012; 64(6): 1554–1559.
11.
BorrelliFIzzoAA. Herb-drug interactions with St John’s wort (Hypericum perforatum): An update on clinical observations. AAPS J2009; 11(4): 710–727.
12.
Van ErpNPBakerSDZandvlietAS. Marginal increase of sunitinib exposure by grapefruit juice. Cancer Chemother Pharmacol2011; 67(3): 695–703.
13.
TangSCLagasJSLankheetNAG. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinib coadministration. Int J Cancer2012; 130(1): 223–233.
14.
TangSCLankheetNAGPollerB. P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict brain accumulation of the active sunitinib metabolite N-desethyl sunitinib. J Pharmacol Exp Ther2012; 341(1): 164–173.
15.
ShuklaSRobeyRWBatesSE. Sunitinib (Sutent, SU11248), a small-molecule receptor tyrosine kinase inhibitor, blocks function of the ATP-binding cassette (ABC) transporters P-glycoprotein (ABCB1) and ABCG2. Drug Metab Dispos2009; 37(2): 359–365.
16.
ManderyKGlaeserHFrommMF. Interaction of innovative small molecule drugs used for cancer therapy with drug transporters. Br J Pharmacol2012; 165(2): 345–362.
17.
FleissigYRegevELehmanH. Sunitinib related osteonecrosis of jaw: A case report. Oral Surg Oral Med Oral Pathol Oral Radiol2012; 113(3): e1–e3.
18.
TroeltzschMWoodlockTKriegelsteinS. Physiology and pharmacology of nonbisphosphonate drugs implicated in osteonecrosis of the jaw. J Can Dent Assoc2012; 78: c85–c85.
19.
RuggieroSLDodsonTBAssaelLA. American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaws –2009 update. J Oral Maxillofac Surg2009; 67(5 Suppl): 2–12.
20.
KollmannsbergerCBjarnasonGBurnettP. Sunitinib in metastatic renal cell carcinoma: Recommendations for management of noncardiovascular toxicities. Oncologist2011; 16(5): 543–553.
21.
RiniBITamaskarIShaheenP. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst2007; 99(1): 81–83.
22.
De GrootJWBLinksTPVan der GraafWTA. Tyrosine kinase inhibitors causing hypothyroidism in a patient on levothyroxine. Ann Oncol2006; 17(11): 1719–1720.
23.
KozloffMChuangEStarrA. An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer. Ann Oncol2010; 21(7): 1436–1441.
24.
De JongeMJADumezHKitzenJJEM. Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours. Eur J Cancer2011; 47(9): 1328–1335.
25.
ReckMFrickhofenNCedresS. Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study. Lung Cancer2010; 70(2): 180–187.
26.
OkamotoIShimizuTMiyazakiM. Feasibility study of two schedules of sunitinib in combination with pemetrexed in patients with advanced solid tumors. Invest New Drugs2012; 30(2): 639–646.
27.
SweeneyCJChioreanEGVerschraegenCF. A phase I study of sunitinib plus capecitabine in patients with advanced solid tumors. J Clin Oncol2010; 28(29): 4513–4520.
28.
BlumenscheinGRCiuleanuTRobertF. Sunitinib plus erlotinib for the treatment of advanced/metastatic non-small-cell lung cancer: A lead-in study. J Thorac Oncol2012; 7(9): 1406–1416.
29.
Gómez-MartínCSalazarRMontagutC. A phase I, dose-finding study of sunitinib combined with cisplatin and 5-fluorouracil in patients with advanced gastric cancer. Invest New Drugs2013; 31(2): 390–398.
30.
BovenEMassardCArmandJP. A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours. Br J Cancer2010; 103(7): 993–1000.
31.
HeathEIBlumenscheinGRCohenRB. Sunitinib in combination with paclitaxel plus carboplatin in patients with advanced solid tumors: Phase I study results. Cancer Chemother Pharmacol2011; 68(3): 703–712.
32.
MolinaAMFeldmanDRVossMH. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma. Cancer2012; 118(7): 1868–1876.
33.
FeldmanDRBaumMSGinsbergMS. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol2009; 27(9): 1432–1439.
34.
BelloCL. Mulay M, Huang X, Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: Pharmacokinetic- pharmacodynamic evaluation of sunitinib. Clin Cancer Res2009; 15(22): 7045–7052.
MachavaramKKGunduJYamsaniMR. Effect of ketoconazole and rifampicin on the pharmacokinetics of ranitidine in healthy human volunteers: A possible role of P-glycoprotein. Drug Metab Drug Interact2006; 22(1): 47–65.
HoK-YGanTJ. Pharmacology, pharmacogenetics, and clinical efficacy of 5-hydroxytryptamine type 3 receptor antagonists for postoperative nausea and vomiting. Curr Opin Anaesthesiol2006; 19(6): 606–611.
40.
ScheenAJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes Metab2010; 12(8): 648–658.
41.
MaBPrueksaritanontTLinJH. Drug interactions with calcium channel blockers: Possible involvement of metabolite-intermediate complexation with CYP3A. Drug Metab Dispos2000; 28(2): 125–130.
42.
BachmakovIWernerUEndressB. Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein. Fundam Clin Pharmacol2006; 20(3): 273–282.
43.
LopezJAHaroldJGRosenthalMC. QT prolongation and torsades de pointes after administration of trimethoprim-sulfamethoxazole. Am J Cardiol1987; 59(4): 376–377.
44.
HaasCEKaufmanDCDiCenzoRC. Effects of metronidazole on hepatic CYP3A4 activity. Pharmacotherapy2001; 21(10): 1192–1195.
45.
RoedlerRNeuhauserMMPenzakSR. Does metronidazole interact with CYP3A substrates by inhibiting their metabolism through this metabolic pathway? Or should other mechanisms be considered?Ann Pharmacother2007; 41(4): 653–658.
46.
HarveyRDOwonikokoTKLewisCM. A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies. Br J Cancer2013; 108(4): 762–765.
47.
HambergPSteeghsNLoosWJ. Decreased exposure to sunitinib due to concomitant administration of ifosfamide: Results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies. Br J C2010; 102(12): 1699–1706.
48.
MotzerRJHudesGWildingG. Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer2009; 7(1): 28–33.
49.
LeeFYFCovelloKLCastanedaS. Synergistic antitumor activity of ixabepilone (BMS-247550) plus bevacizumab in multiple in vivo tumor models. Clin Cancer Res2008; 14(24): 8123–8131.
50.
AmundsenRÅsbergAOhmIK. Cyclosporine-A and tacrolimus-mediated inhibition of CYP3A4 and CYP3A5 in vitro. Drug Metab Dispos2012; 40(4): 655–661.
51.
SausseleTBurkOBlievernichtJK. Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole. Clin Pharmacol Ther2007; 82(3): 265–274.
52.
Wenzel-SeifertKWittmannMHaenE. QTc prolongation by psychotropic drugs and the risk of Torsade de Pointes. Dtsch Arztebl Int2011; 108(41): 687–693.
53.
FischerEGregusZVargaF. Effects of barbiturates on the hepatic cytochrome P-450 dependent enzyme system and biliary excretion of exogenous organic anions in rats. Digestion1980; 20(2): 115–120.
54.
International Registry for Drug-Induced Arrhythmias; University of Arizona Health Sciences Center, Tucson, AR. http://www.qtdrugs.org (accessed September 2012).
