Marginal Increase of Sunitinib Exposure by Grapefruit Juice

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2010 Jun 1

PMID 20512335

Citations 17

Authors

Nielka P van Erp

Sharyn D Baker

Anthe S Zandvliet

Bart A Ploeger

Margaret den Hollander

Zhaoyuan Chen

Jan den Hartigh

Jacqueline M C Konig-Quartel

Henk-Jan Guchelaar

Hans Gelderblom

Affiliations

Soon will be listed here.

Abstract

Purpose: The drug label of sunitinib includes a warning for concomitant use of grapefruit juice (GJ) but clinical evidence for this drug interaction is lacking. The aim of this study is to determine the effect of GJ, a potent intestinal cytochrome P450 (CYP) 3A4 inhibitor, on steady-state sunitinib pharmacokinetics (PK).

Methods: Sunitinib PK was evaluated in eight cancer patients receiving sunitinib monotherapy in a "4 weeks on-2 weeks off" dose regimen. Serial blood samples for PK analysis of sunitinib were collected on two separate days. On both PK days, patients received a single oral dose of 7.5-mg midazolam as a phenotypic probe for assessment of intestinal CYP3A4 activity. The first PK day was at steady-state sunitinib PK (between days 14-20), the second PK day was on day 28. On days 25, 26 and 27, 200-mL GJ was consumed 3 times a day. The effect of GJ on sunitinib exposure was assessed by comparing sunitinib PK with and without GJ.

Results: Concomitant use of GJ and sunitinib resulted in an 11% increase of the relative bioavailability of sunitinib (P < 0.05). The effect of GJ on CYP3A4 activity was confirmed by an increase of ~50% of mean midazolam exposure (AUC(0-24 h)) from 122.1 to 182.0 ng h/mL (P = 0.034).

Conclusion: GJ consumption results in a marginal increase in sunitinib exposure which is not considered clinically relevant. There is no clinical evidence underscoring the warning in the sunitinib drug label regarding concomitant use of GJ.

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References

Dresser G, Bailey D, Leake B, Schwarz U, Dawson P, Freeman D . Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther. 2002; 71(1):11-20. DOI: 10.1067/mcp.2002.121152. View

Franke R, Baker S, Mathijssen R, Schuetz E, Sparreboom A . Influence of solute carriers on the pharmacokinetics of CYP3A4 probes. Clin Pharmacol Ther. 2008; 84(6):704-9. DOI: 10.1038/clpt.2008.94. View

Goodman V, Rock E, Dagher R, Ramchandani R, Abraham S, Gobburu J . Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res. 2007; 13(5):1367-73. DOI: 10.1158/1078-0432.CCR-06-2328. View

Reif S, Nicolson M, Bisset D, Reid M, Kloft C, Jaehde U . Effect of grapefruit juice intake on etoposide bioavailability. Eur J Clin Pharmacol. 2002; 58(7):491-4. DOI: 10.1007/s00228-002-0495-9. View

Demetri G, van Oosterom A, Garrett C, Blackstein M, Shah M, Verweij J . Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006; 368(9544):1329-38. DOI: 10.1016/S0140-6736(06)69446-4. View

Paine M, Widmer W, Hart H, Pusek S, Beavers K, Criss A . A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction. Am J Clin Nutr. 2006; 83(5):1097-105. DOI: 10.1093/ajcn/83.5.1097. View

Paine M, Widmer W, Pusek S, Beavers K, Criss A, Snyder J . Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine. Am J Clin Nutr. 2008; 87(4):863-71. DOI: 10.1093/ajcn/87.4.863. View

Bello C, Sherman L, Zhou J, Verkh L, Smeraglia J, Mount J . Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs. 2006; 17(3):353-8. DOI: 10.1097/00001813-200603000-00015. View

Motzer R, Hutson T, Tomczak P, Michaelson M, Bukowski R, Rixe O . Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007; 356(2):115-24. DOI: 10.1056/NEJMoa065044. View

10.

Yin O, Gallagher N, Li A, Zhou W, Harrell R, Schran H . Effect of grapefruit juice on the pharmacokinetics of nilotinib in healthy participants. J Clin Pharmacol. 2009; 50(2):188-94. DOI: 10.1177/0091270009336137. View

11.

Fuhr U, Jetter A, Kirchheiner J . Appropriate phenotyping procedures for drug metabolizing enzymes and transporters in humans and their simultaneous use in the "cocktail" approach. Clin Pharmacol Ther. 2007; 81(2):270-83. DOI: 10.1038/sj.clpt.6100050. View

12.

Eagling V, Profit L, Back D . Inhibition of the CYP3A4-mediated metabolism and P-glycoprotein-mediated transport of the HIV-1 protease inhibitor saquinavir by grapefruit juice components. Br J Clin Pharmacol. 1999; 48(4):543-52. PMC: 2014377. DOI: 10.1046/j.1365-2125.1999.00052.x. View

13.

Greenblatt D, von Moltke L, Harmatz J, Chen G, Weemhoff J, Jen C . Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice. Clin Pharmacol Ther. 2003; 74(2):121-9. DOI: 10.1016/S0009-9236(03)00118-8. View

14.

Minkin P, Zhao M, Chen Z, Ouwerkerk J, Gelderblom H, Baker S . Quantification of sunitinib in human plasma by high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008; 874(1-2):84-8. PMC: 2612784. DOI: 10.1016/j.jchromb.2008.09.007. View

15.

Culm-Merdek K, von Moltke L, Gan L, Horan K, Reynolds R, Harmatz J . Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir. Clin Pharmacol Ther. 2006; 79(3):243-54. DOI: 10.1016/j.clpt.2005.11.009. View

16.

Wang E, Casciano C, Clement R, Johnson W . Inhibition of P-glycoprotein transport function by grapefruit juice psoralen. Pharm Res. 2001; 18(4):432-8. DOI: 10.1023/a:1011089924099. View

17.

Goosen T, Cillie D, Bailey D, Yu C, He K, Hollenberg P . Bergamottin contribution to the grapefruit juice-felodipine interaction and disposition in humans. Clin Pharmacol Ther. 2004; 76(6):607-17. DOI: 10.1016/j.clpt.2004.08.019. View

18.

van Erp N, Gelderblom H, Karlsson M, Li J, Zhao M, Ouwerkerk J . Influence of CYP3A4 inhibition on the steady-state pharmacokinetics of imatinib. Clin Cancer Res. 2007; 13(24):7394-400. DOI: 10.1158/1078-0432.CCR-07-0346. View

19.

Shukla S, Robey R, Bates S, Ambudkar S . 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 Dispos. 2008; 37(2):359-65. PMC: 2680522. DOI: 10.1124/dmd.108.024612. View

20.

de Castro W, Mertens-Talcott S, Rubner A, Butterweck V, Derendorf H . Variation of flavonoids and furanocoumarins in grapefruit juices: a potential source of variability in grapefruit juice-drug interaction studies. J Agric Food Chem. 2006; 54(1):249-55. DOI: 10.1021/jf0516944. View