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

Eur J Clin Pharmacol. 1999 Jan;54(11):857-64. doi: 10.1007/s002280050567.

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 x h x 1(-1) to 124 (92-239) mg x h x 1(-1). For the (R)-isomer, the AUC increase from 96 (70-142) mg x h x 1(-1) in the absence to 108 (75-155) mg x h x 1(-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anticoagulants / pharmacokinetics
  • Anticoagulants / pharmacology*
  • Blood Coagulation Factors / metabolism*
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Factor VII / metabolism
  • Humans
  • Male
  • Models, Biological
  • Phenprocoumon / pharmacokinetics
  • Phenprocoumon / pharmacology*
  • Piroxicam / analogs & derivatives*
  • Piroxicam / pharmacology
  • Prothrombin / metabolism
  • Prothrombin Time

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticoagulants
  • Blood Coagulation Factors
  • Piroxicam
  • Factor VII
  • Prothrombin
  • lornoxicam
  • Phenprocoumon