Objective  Nebicapone is a new catechol-O-methyltransferase inhibitor. In vitro, nebicapone has showed an inhibitory effect upon CYP2C9, which is responsible for the metabolism of S-warfarin. The objective of this study was to investigate the effect of nebicapone on warfarin pharmacokinetics and pharmacodynamics in healthy subjects.

Methods  Single-centre, open-label, randomised, two-period crossover study in 16 healthy volunteers. In one period, subjects received nebicapone 200 mg thrice daily for 9 days and a racemic warfarin 25-mg single dose concomitantly with the nebicapone morning dose on day 4 (test). In the other period, subjects received a racemic warfarin 25-mg single dose alone (reference). The treatment periods were separated by a washout of 14 days.

Results  For R-warfarin, mean ± SD C_max was 1,619 ± 284 ng/mL for test and 1,649 ± 357 ng/mL for reference, while AUC_0-t was 92,796 ± 18,976 ng·h/mL (test) and 73,597 ± 11,363 ng·h/mL (reference). The R-warfarin test-to-reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) were 0.973 (0.878–1.077) for C_max and 1.247 (1.170–1.327) for AUC_0-t . For S-warfarin, mean ± SD C_max was 1,644 ± 331 ng/mL for test and 1,739 ± 392 ng/mL for reference, while AUC_0-t was 66,627 ± 41,199 ng·h/mL (test) and 70,178 ± 42,560 ng·h/mL (reference). The S-warfarin test-to-reference GMR and 90%CI were 0.932 (0.845–1.028) for C_max and 0.914 (0.875–0.954) for AUC_0-t . No differences were found for the pharmacodynamic parameter (INR).

Conclusion  Nebicapone showed no significant effect on S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found but is unlikely to be of clinical relevance