Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 5, pp 1143–1147 | Cite as

Calcium carbonate does not affect nilotinib pharmacokinetics in healthy volunteers

  • Hussein A. Tawbi
  • An L. Tran
  • Susan M. Christner
  • Yan Lin
  • Matthew Johnson
  • Emily Mowrey
  • Leonard R. Appleman
  • Ronald Stoller
  • Brian M. Miller
  • Merrill J. Egorin
  • Jan H. Beumer
Short Communication

Abstract

What is already known about this subject

Gastric upset is a common side effect of nilotinib therapy, and calcium carbonate is frequently used concomitantly, either as antacid or as calcium supplementation. With the increasing number of oral agents in cancer therapy, oral drug–drug interactions are becoming more relevant. Nilotinib has already been shown to be absorbed to a much lesser extent when co-administered with proton pump inhibitors. Because exposure to sub-therapeutic concentrations of anticancer drugs such as nilotinib may result in selection of resistant clones and ultimately relapse, we studied the effect of a calcium carbonate supplement (Tums Ultra 1000®) on nilotinib pharmacokinetics.

What this study adds

Calcium carbonate may be co-administered with nilotinib without significantly affecting the pharmacokinetics of nilotinib and potentially impacting efficacy.

Purpose

Nilotinib is a second-generation oral tyrosine kinase inhibitor with superior efficacy compared with imatinib mesylate in the treatment for chronic phase chronic myelogenous leukemia. Calcium carbonate is commonly used as a source of calcium supplementation or as antacid to ameliorate the gastrointestinal side effects associated with nilotinib, which could have unknown effects on nilotinib absorption. The purpose of this study was to provide information on the effect of calcium carbonate on the PK of nilotinib in healthy volunteers.

Methods

Healthy subjects were enrolled in a two-period, open-label, single-institution, randomized, cross-over, fixed-schedule study. In one period, each subject received 400 mg of nilotinib p.o. In the other period, 4,000 mg of calcium carbonate (4 X Tums Ultra 1000®) was administered p.o. 15 min prior to the nilotinib dose. Plasma samples were collected at specified timepoints, concentrations of nilotinib were quantitated by LC–MS, and data were analyzed non-compartmentally.

Results

Eleven subjects were evaluable. Calcium supplementation did not significantly affect nilotinib pharmacokinetic parameters including area under the plasma concentration versus time curve (18.4 μg/mL h alone vs. 16.9 μg/mL h with calcium carbonate, p = 0.83; 80 % power); maximum plasma concentration (C max) (0.670 μg/mL alone vs. 6.18 μg/mL with calcium carbonate, p = 0.97); or half-life (18.9 h alone vs. 17.2 h with calcium carbonate, p = 0.18).

Conclusions

Our results indicate that the use of calcium carbonate does not significantly affect nilotinib pharmacokinetics.

Keywords

Nilotinib Calcium CML Interaction 

Notes

Acknowledgments

We thank the nursing staff of the University of Pittsburgh Clinical Translational Research Center for their invaluable assistance and the University of Pittsburgh Cancer Institute Merrill Egorin Writing Group for constructive suggestions regarding the manuscript. This work was supported by Novartis Pharmaceuticals Corporation (East Hanover, NJ, USA) and NIH/NCRR/CTSA Grant UL1 RR024153. This project used the UPCI Clinical Pharmacology Analytical Facility (CPAF) and was supported in part by award P30CA047904.

References

  1. 1.
    Saglio G, Kim DW, Issaragrisil S, Le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP, Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259PubMedCrossRefGoogle Scholar
  2. 2.
    Kantarjian HM, Hochhaus A, Saglio G, De SC, Flinn IW, Stenke L, Goh YT, Rosti G, Nakamae H, Gallagher NJ, Hoenekopp A, Blakesley RE, Larson RA, Hughes TP (2011) Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol 12:841–851PubMedCrossRefGoogle Scholar
  3. 3.
    Cho JH, Kim KM, Kwon M, Kim JH, Lee J (2011) Nilotinib in patients with metastatic melanoma harboring KIT gene aberration. Invest New Drugs 30(5):2008–2014PubMedCrossRefGoogle Scholar
  4. 4.
    Sawaki A, Nishida T, Doi T, Yamada Y, Komatsu Y, Kanda T, Kakeji Y, Onozawa Y, Yamasaki M, Ohtsu A (2011) Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer 117(20):4633–4641PubMedCrossRefGoogle Scholar
  5. 5.
    Ravaud A, Bello CL (2011) Exposure-response relationships in patients with metastatic renal cell carcinoma receiving sunitinib: maintaining optimum efficacy in clinical practice. Anticancer Drugs 22:377–383PubMedCrossRefGoogle Scholar
  6. 6.
    Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, Gathmann I, Wang Y (2008) Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood 111:4022–4028PubMedCrossRefGoogle Scholar
  7. 7.
    Demetri GD, Wang Y, Wehrle E, Blanke C, Joensuu H, von Mehren M (2008) Correlation of imatinib plasma levels with clinical benefit in patients (Pts) with unresectable/metastatic gastrointestinal stromal tumors (GIST). In: ASCO gastrointestinal cancers symposiumGoogle Scholar
  8. 8.
    Kantarjian H, Giles F, Wunderle L, Bhalla K, O’Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG (2006) Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med 354:2542–2551PubMedCrossRefGoogle Scholar
  9. 9.
    Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF (2004) Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999–2000. Am J Epidemiol 160:339–349PubMedCrossRefGoogle Scholar
  10. 10.
    Straub DA (2007) Calcium supplementation in clinical practice: a review of forms, doses, and indications. Nutr Clin Pract 22:286–296PubMedCrossRefGoogle Scholar
  11. 11.
    Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, Benson K, Leighton J, Kim SK, Wood R, Rothmann M, Chen G, KM U, Staten AM, Pazdur R (2002) Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 8:935–942Google Scholar
  12. 12.
    Parise RA, Egorin MJ, Christner SM, Shah DD, Zhou W, Beumer JH (2009) A high-performance liquid chromatography-mass spectrometry assay for quantitation of the tyrosine kinase inhibitor nilotinib in human plasma and serum. J Chromatogr B Analyt Technol Biomed Life Sci 877:1894–1900PubMedCrossRefGoogle Scholar
  13. 13.
    de Campos DR, Vieira NR, Bernasconi G, Barros FA, Meurer EC, Marchioretto MA, Coelho EC, Calafatti SA, Sommer C, Couto JM, Buranello S, Silva AR, Amarante AR, Abib E, Junior JP (2007) Bioequivalence of two enteric coated formulations of pantoprazole in healthy volunteers under fasting and fed conditions. Arzneimittelforschung 57:309–314PubMedGoogle Scholar
  14. 14.
    Sparano BA, Egorin MJ, Parise RA, Walters J, Komazec KA, Redner RL, Beumer JH (2009) Effect of antacid on imatinib absorption. Cancer Chemother Pharmacol 63:525–528PubMedCrossRefGoogle Scholar
  15. 15.
    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 50:960–967PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Hussein A. Tawbi
    • 1
    • 2
  • An L. Tran
    • 2
  • Susan M. Christner
    • 1
  • Yan Lin
    • 3
  • Matthew Johnson
    • 4
  • Emily Mowrey
    • 4
  • Leonard R. Appleman
    • 2
  • Ronald Stoller
    • 2
  • Brian M. Miller
    • 5
  • Merrill J. Egorin
    • 1
    • 2
    • 6
  • Jan H. Beumer
    • 1
    • 7
  1. 1.Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  2. 2.Division of Hematology/Oncology, Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of BiostatisticsUniversity of PittsburghPittsburghUSA
  4. 4.Clinical Research ServicesUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  5. 5.Investigational Drug ServiceUPMC Cancer CentersPittsburghUSA
  6. 6.Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  7. 7.Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA

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