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Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors

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Abstract

Purpose

The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites.

Methods

In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day.

Results

Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration–time curve 24 h post-dose (AUC(0–24)) and mean maximum observed concentration (C max) of pazopanib increased by 66 and 45 %, respectively; mean AUC(0–24) and C max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC(0–24) and C max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased.

Conclusions

Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.

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References

  1. Harris PA, Boloor A, Cheung M et al (2008) Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 51:4632–4640

    Article  PubMed  CAS  Google Scholar 

  2. Sternberg CN, Davis ID, Mardiak J et al (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 28:1061–1068

    Article  PubMed  CAS  Google Scholar 

  3. van der Graaf WT, Blay JY, Chawla SP et al (2012) Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 379:1879–1886

    Article  PubMed  Google Scholar 

  4. Hurwitz HI, Dowlati A, Saini S, Savage S, Suttle AB, Gibson DM, Hodge JP, Merkle EM, Pandite L (2009) Phase I trial of pazopanib in patients with advanced cancer. Clin Cancer Res 15:4220–4227

    Article  PubMed  CAS  Google Scholar 

  5. Goh BC, Reddy NJ, Dandamudi UB et al (2010) An evaluation of the drug interaction potential of pazopanib, an oral vascular endothelial growth factor receptor tyrosine kinase inhibitor, using a modified Cooperstown 5 + 1 cocktail in patients with advanced solid tumors. Clin Pharmacol Ther 88:652–659

    Article  PubMed  CAS  Google Scholar 

  6. Abbas R, Hug BA, Leister C, Burns J, Sonnichsen D (2011) Pharmacokinetics of oral neratinib during co-administration of ketoconazole in healthy subjects. Br J Clin Pharmacol 71:522–527

    Article  PubMed  CAS  Google Scholar 

  7. Dutreix C, Peng B, Mehring G, Hayes M, Capdeville R, Pokorny R, Seiberling M (2004) Pharmacokinetic interaction between ketoconazole and imatinib mesylate (Glivec) in healthy subjects. Cancer Chemother Pharmacol 54:290–294

    Article  PubMed  CAS  Google Scholar 

  8. Johnson FM, Agrawal S, Burris H et al (2010) Phase 1 pharmacokinetic and drug-interaction study of dasatinib in patients with advanced solid tumors. Cancer 116:1582–1591

    Article  PubMed  CAS  Google Scholar 

  9. Di Gion P, Kanefendt F, Lindauer A, Scheffler M, Doroshyenko O, Fuhr U, Wolf J, Jaehde U (2011) Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. Clin Pharmacokinet 50:551–603

    Article  PubMed  Google Scholar 

  10. Miner P Jr, Katz PO, Chen Y, Sostek M (2003) Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 98:2616–2620

    Article  PubMed  CAS  Google Scholar 

  11. Yin OQ, Gallagher N, Fischer D, Demirhan E, Zhou W, Golor G, Schran H (2010) Effect of the proton pump inhibitor esomeprazole on the oral absorption and pharmacokinetics of nilotinib. J Clin Pharmacol 50:960–967

    Article  PubMed  CAS  Google Scholar 

  12. Kapadia S, Hapani S, Wu S (2011) Risk of high-grade liver toxicity with pazopanib in patients with cancer: a meta-analysis. J Clin Oncol 29(suppl):abstract 4595

    Google Scholar 

  13. Olkkola KT, Backman JT, Neuvonen PJ (1994) Midazolam should be avoided in patients receiving the systemic antimycotics ketoconazole or itraconazole. Clin Pharmacol Ther 55:481–485

    Article  PubMed  CAS  Google Scholar 

  14. Bjornsson TD, Callaghan JT, Einolf HJ et al (2003) The conduct of in vitro and in vivo drug–drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31:815–832

    Article  PubMed  CAS  Google Scholar 

  15. Heath EI, Chiorean EG, Sweeney CJ et al (2010) A phase I study of the pharmacokinetic and safety profiles of oral pazopanib with a high-fat or low-fat meal in patients with advanced solid tumors. Clin Pharmacol Ther 88:818–823

    Article  PubMed  CAS  Google Scholar 

  16. Warrington S, Baisley K, Boyce M, Tejura B, Morocutti A, Miller N (2002) Effects of rabeprazole, 20 mg, or esomeprazole, 20 mg, on 24-h intragastric pH and serum gastrin in healthy subjects. Aliment Pharmacol Ther 16:1301–1307

    Article  PubMed  CAS  Google Scholar 

  17. Wilder-Smith C, Rohss K, Bokelund Singh S, Sagar M, Nagy P (2010) The effects of dose and timing of esomeprazole administration on 24-h, daytime and night-time acid inhibition in healthy volunteers. Aliment Pharmacol Ther 32:1249–1256

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Financial support for this study and for medical editorial assistance was provided by Glaxo SmithKline Pharmaceuticals, Philadelphia, Pennsylvania. We thank William Sinkins, PhD, ProEd Communications, Inc., for his medical editorial assistance with this manuscript.

Conflict of interest

Authors Suttle and Tada are GlaxoSmithKline employees and stockholders. Author Botbyl’s company, Provonix, provides data services to GlaxoSmithKline. Author Tan has received research funding from GlaxoSmithKline. All other authors report no potential conflict of interest.

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Authors and Affiliations

  1. The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA

    Antoinette R. Tan, Darlene G. Gibbon, Mark N. Stein & Diana Lindquist

  2. Institute for Translational Oncology Research, Greenville, SC, USA

    Jeffery W. Edenfield, Julie C. Martin, Charles Gregory & Joseph J. Stephenson

  3. GlaxoSmithKline, Research Triangle Park, NC, USA

    A. Benjamin Suttle & Hiroomi Tada

  4. Provonix, Mullica Hill, NJ, USA

    Jeffrey Botbyl

Authors
  1. Antoinette R. Tan
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  2. Darlene G. Gibbon
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  3. Mark N. Stein
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  4. Diana Lindquist
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  5. Jeffery W. Edenfield
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  6. Julie C. Martin
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  7. Charles Gregory
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  8. A. Benjamin Suttle
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  9. Hiroomi Tada
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  10. Jeffrey Botbyl
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  11. Joseph J. Stephenson
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Corresponding author

Correspondence to Antoinette R. Tan.

Additional information

Clinical Trials Registration Number: NCT01205230.

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Tan, A.R., Gibbon, D.G., Stein, M.N. et al. Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors. Cancer Chemother Pharmacol 71, 1635–1643 (2013). https://doi.org/10.1007/s00280-013-2164-3

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  • DOI: https://doi.org/10.1007/s00280-013-2164-3

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