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Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin

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Abstract

Objective

To examine the effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Aprepitant is a neurokinin-1 (NK1)-receptor antagonist developed as an antiemetic for chemotherapy-induced nausea and vomiting.

Methods

This was a double-blind, placebo-controlled, randomized, two-period, parallel-group study. During period 1, warfarin was individually titrated to a stable prothrombin time (expressed as international normalized ratio, INR) from 1.3 to 1.8. Subsequently, the daily warfarin dose remained fixed for 10–12 days. During period 2, the warfarin dose was continued for 8 days, and on days 1–3 administered concomitantly with aprepitant (125 mg on day 1, and 80 mg on days 2 and 3) or placebo. At baseline (day −1 of period 2) and on day 3, warfarin pharmacokinetics was investigated. INR was monitored daily. During period 2, warfarin trough concentrations were determined daily.

Results

The study was completed by 22 healthy volunteers (20 men, 2 women). On day 3, steady-state pharmacokinetics of warfarin enantiomers after aprepitant did not change, as assessed by warfarin AUC0-24h and Cmax. However, compared with placebo, trough S(−) warfarin concentrations decreased on days 5–8 (maximum decrease 34% on day 8, P<0.01). The INR decreased after aprepitant with a mean maximum decrease on day 8 of 11% versus placebo (P=0.011).

Conclusion

These data are consistent with a significant induction of CYP2C9 metabolism of S(−) warfarin by aprepitant. Subsequently, in patients on chronic warfarin therapy, the clotting status should be monitored closely during the 2-week period, particularly at 7–10 days, following initiation of the 3-day regimen of aprepitant with each chemotherapy cycle.

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Acknowledgements

This study was supported by a grant from Merck and Co. Inc., NJ, USA.

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Authors and Affiliations

  1. Center for Clinical Pharmacology, U. Z. Gasthuisberg (K. U. Leuven), Herestraat 49, B-3000, Leuven, Belgium

    M. Depré, A. Van Hecken, M. Oeyen & J. N. de Hoon

  2. Merck Research Laboratories, Brussels, Belgium

    I. De Lepeleire & T. Laethem

  3. Merck Research Laboratories, Rahway, NJ, USA

    P. Rothenberg & T. Crumley

  4. Merck Research Laboratories, Blue Bell, PA, USA

    K. J. Petty & D. Panebianco

  5. Merck Research Laboratories, West Point, PA, USA

    A. Majumdar & A. Bergman

Authors
  1. M. Depré
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  2. A. Van Hecken
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  3. M. Oeyen
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  4. I. De Lepeleire
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  5. T. Laethem
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  6. P. Rothenberg
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  7. K. J. Petty
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  8. A. Majumdar
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  9. T. Crumley
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  10. D. Panebianco
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  11. A. Bergman
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  12. J. N. de Hoon
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Correspondence to M. Depré.

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Depré, M., Van Hecken, A., Oeyen, M. et al. Effect of aprepitant on the pharmacokinetics and pharmacodynamics of warfarin. Eur J Clin Pharmacol 61, 341–346 (2005). https://doi.org/10.1007/s00228-005-0907-8

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  • DOI: https://doi.org/10.1007/s00228-005-0907-8

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