This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Camidge, R. Articles by Jodrell, D. Search for Related Content PubMed PubMed Citation Articles by Camidge, R. Articles by Jodrell, D. Social Bookmarking                            What's this?

Significant Effect of Capecitabine on the Pharmacokinetics and Pharmacodynamics of Warfarin in Patients With Cancer

From the Cancer Research UK Centre, Edinburgh; Aberdeen Royal Infirmary, Aberdeen, Scotland; Departments of Clinical Pharmacology; Department of Statistics, F. Hoffmann-La Roche Ltd, Basel, Switzerland

Address reprint requests to Duncan Jodrell, MD, University of Edinburgh Cancer Research Centre, Crewe Rd S, Edinburgh, EH4 2XR, Scotland; e-mail: duncan.jodrell{at}cancer.org.uk

PURPOSE: Clinical cases of capecitabine and other fluorouracil-based chemotherapies potentiating the effects of coumarin derivatives have been reported. This study assessed the influence of capecitabine on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin.

PATIENTS AND METHODS: Four patients with advanced/metastatic cancer completed the study, receiving a single oral dose of 20 mg warfarin before the start of standard capecitabine treatment (day 1), and again during the third cycle of capecitabine (day 61). PK parameters of warfarin and capecitabine and PD parameters of warfarin were assessed on days 1 and 61.

RESULTS: During capecitabine treatment, the area under the plasma concentration time curve from 0 to infinity (AUC_0-) of S-warfarin increased by 57% (90% CI, 32% to 88%) with a 51% prolongation of the elimination half-life (t_1/2; 90% CI, 32% to 74%). Exposure to R-warfarin was not significantly affected. Plasma concentrations of capecitabine and its metabolites were not influenced by warfarin. During capecitabine treatment, the effect of warfarin on the baseline corrected AUC of the International Normalized Ratio (INR) increased by 2.8 times (90% CI, 1.33 to 5.70), with the maximum observed INR value almost doubling. Because of the administration of vitamin K to some patients with elevated INRs, these figures are likely to underestimate the true PD effect. Mean baseline factor VII levels dropped while on capecitabine therapy, potentially contributing to the observed PD interaction, though this effect did not reach statistical significance.

CONCLUSION: There is a significant pharmacokinetic interaction between capecitabine and S-warfarin, resulting in exaggerated anticoagulant activity. Patients receiving warfarin anticoagulant therapy concomitantly with capecitabine should have their INR closely monitored and warfarin doses adjusted accordingly.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				A. A. Khorana Cancer and thrombosis: implications of published guidelines for clinical practice Ann. Onc., October 1, 2009; 20(10): 1619 - 1630. [Abstract] [Full Text] [PDF]

				C.-M. Wong, Y. Ko, and A. Chan Clinically Significant Drug-Drug Interactions Between Oral Anticancer Agents and Nonanticancer Agents: Profiling and Comparison of Two Drug Compendia Ann. Pharmacother., December 1, 2008; 42(12): 1737 - 1748. [Abstract] [Full Text] [PDF]

				R. P. Riechelmann, I. F. Tannock, L. Wang, E. D. Saad, N. A. Taback, and M. K. Krzyzanowska Potential Drug Interactions and Duplicate Prescriptions Among Cancer Patients J Natl Cancer Inst, April 18, 2007; 99(8): 592 - 600. [Abstract] [Full Text] [PDF]

				D. Crivellari, D. Lombardi, G. Corona, C. Massacesi, R. Talamini, R. Sorio, M. D. Magri, C. Lestuzzi, A. Lucenti, A. Veronesi, et al. Innovative schedule of oral idarubicin in elderly patients with metastatic breast cancer: comprehensive results of a phase II multi-institutional study with pharmacokinetic drug monitoring Ann. Onc., May 1, 2006; 17(5): 807 - 812. [Abstract] [Full Text] [PDF]