European Journal of Clinical Pharmacology

, Volume 54, Issue 11, pp 857–864 | Cite as

Opposite effects of lornoxicam co-administration on phenprocoumon pharmacokinetics and pharmacodynamics

  • U. P. Masche
  • K. M. Rentsch
  • A. von Felten
  • P. J. Meier
  • K. E. Fattinger
PHARMACOKINETICS AND DISPOSITION

Abstract

Objective: To investigate the effect of co-administration of the non-steroidal anti-inflammatory drug (NSAID) lornoxicam on the pharmacokinetics of (R)- and (S)-phenprocoumon and their effect on factor II and VII activities.

Methods: Six healthy male volunteers completed an open crossover study. Plasma concentrations of (R)- and (S)-phenprocoumon and activities of coagulation factors II and VII were measured after a single oral dose of 9 mg phenprocoumon racemate. In the second session, lornoxicam administration was started 3 days before phenprocoumon administration and continued twice daily until the last blood sample was drawn.

Results: Lornoxicam co-administration resulted in a statistically significant increase of the area under the concentration-time curve (AUC) of the more potent (S)-isomer of phenprocoumon from a median value of 100 (range 68–146) mg · h · l−1 to 124 (92–239) mg · h · l−1. For the (R)-isomer, the AUC increase from 96 (70–142) mg h · l−1 in the absence to 108 (75–155) mg · h · l−1 in the presence of lornoxicam was not statistically significant. In a model-based analysis, an increase of (S)-phenprocoumon and (R)-phenprocoumon bioavailability of 14% [95% CI (9%, 19%)] and 6% (2%, 10%) and a decrease of their clearances by 15% (8%, 21%) and 6% (0%, 13%) was obtained. Lornoxicam co-administration did not influence the free fractions of (R)- or (S)-phenprocoumon. Contrary to what was expected from the changes in pharmacokinetics, a statistically significant decrease in the effect of phenprocoumon on factor II and VII activity was observed for the sessions with lornoxicam co-administration. For factor VII, lornoxicam was found to increase the concentration causing half-maximal effect (C50) of phenprocoumon by 70% [95% CI (38%, 111%)].

Conclusion: Co-administration of lornoxicam at the upper limit of recommended doses mainly altered the pharmacokinetics of the more potent (S)-isomer and to a lesser degree those of (R)-phenprocoumon. Despite these changes in pharmacokinetics, a decrease of the effect on factor II and VII activity was observed. These results suggest that in the case of lornoxicam co-administration in a patient treated with phenprocoumon the prothrombin time should be monitored closely.

Key words Drug interaction Oral anticoagulants NSAID 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • U. P. Masche
    • 1
  • K. M. Rentsch
    • 2
  • A. von Felten
    • 3
  • P. J. Meier
    • 1
  • K. E. Fattinger
    • 1
  1. 1.Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital, Rämistrasse 100, CH-8091 Zürich, Switzerland e-mail: fattinge@kpt.unizh.ch Tel.: +41-1-255-20-67, Fax: +41-1-255-44-11CH
  2. 2.Institute of Clinical Chemistry, University Hospital, Zürich, SwitzerlandCH
  3. 3.Laboratory of Blood Coagulation, Department of Internal Medicine, University Hospital, Zürich, SwitzerlandCH

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