The effect of rofecoxib on the pharmacodynamics and pharmacokinetics of warfarin

Abstract

Rofecoxib increased plasma concentrations of the biologically less active R(+) warfarin, which accounted for a small increase in INR. The approximately 8% increase in INR at steady state with warfarin co-administered with 25 mg of rofecoxib is not likely to be clinically important in most patients taking warfarin. However, standard monitoring of INR values should be conducted when therapy with rofecoxib is initiated or changed, particularly in the first few days, for patients receiving warfarin.

Rofecoxib Is a Potent, Metabolism-Dependent Inhibitor of CYP1A2: Implications for in Vitro Prediction of Drug Interactions

“…Prediction of in vivo interactions on the basis of these values (Fig. 4), and the free C max of rofecoxib, 0.15 M with 25 mg of rofecoxib daily (Merck & Co., 2002;Backman et al, 2006b), conformed fairly well, but not exactly, with the findings of the pharmacokinetic studies with tizanidine, theophylline, and R-warfarin (Schwartz et al, 2000;Bachmann et al, 2003;Backman et al, 2006b). The fraction of the substrate metabolized by CYP1A2 (f m ⅐ f m,CYP1A2 ) is crucial for in vitro-in vivo extrapolations.…”

“…However, the inhibition of CYP1A2 by rofecoxib is clinically relevant as documented by the clinical studies with tizanidine, theophylline, and warfarin (Schwartz et al, 2000;Bachmann et al, 2003;Backman et al, 2006b). It is likely that the metabolism of other CYP1A2 substrate drugs also is markedly inhibited by rofecoxib.…”

“…The f m ⅐ f m,CYP1A2 values for tizanidine, theophylline, and R-warfarin are approximately 0.98, 0.7, and Յ0.4, respectively (Kaminsky and Zhang, 1997;Rasmussen et al, 1997;Yao et al, 2001;Granfors et al, 2004b;Backman et al, 2006a). In the in vivo studies with healthy volunteers, rofecoxib (25 mg daily) has raised the AUC of tizanidine, theophylline and R-warfarin 13.6-fold, 1.51-fold, and 1.38-fold, respectively (Schwartz et al, 2000;Bachmann et al, 2003;Backman et al, 2006b). Thus, our predictions seem to slightly underestimate the interaction with tizanidine (8-fold predicted increase in AUC), and overestimate the interactions with theophylline (2.6-fold predicted increase) and R-warfarin (1.54-fold predicted increase).…”

“…In previous pharmacokinetic studies, rofecoxib has moderately increased the plasma concentrations of R-warfarin and theophylline (Schwartz et al, 2000;Bachmann et al, 2003), and greatly increased the plasma concentrations of tizanidine (Backman et al, 2006b). In the present in vitro study, we wanted to elucidate the mechanism of these interactions by studying the effect of rofecoxib on CYP1A2 activity (phenacetin O-deethylation) in human liver microsomes.…”

“…Rofecoxib is a cyclooxygenase-2-selective nonsteroidal anti-inflammatory drug, which was recently withdrawn, possibly temporarily, from clinical use because of its cardiovascular side effects. Previous studies have shown that rofecoxib moderately increases plasma concentrations and effects of theophylline (Bachmann et al, 2003) and the R-isomer of warfarin (Schwartz et al, 2000). Quite recently, rofecoxib in therapeutic doses of 25 mg per day was found to increase more than 10-fold the plasma concentrations of the CYP1A2 substrate tizanidine in humans (Backman et al, 2006b).…”