Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects

• Type: Article in International Scientific Journal
• Date: 2008

Authors

Almeida, L (Author) Other; Falcao, A (Author) Other; Vaz Da Silva, M (Author) FMUP; Nunes, T (Author) Other; Santos, AT (Author) Other; Rocha, JF (Author) Other; Neta, C (Author) Other; Macedo, T (Author) Other; Fontes Ribeiro, C (Author) Other; soares-da-silva, p (Author) FMUP

Journal

Title: European Journal of Clinical Pharmacology

Vol. 64

Pages: 961-966

ISSN: 0031-6970

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 6 Citations

Scopus - 6 Citations

Other information

Authenticus ID: P-003-VR5

DOI: 10.1007/s00228-008-0534-2

Abstract (EN): 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 center dot h/mL (test) and 73,597 +/- 11,363 ng center dot 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 Cmax 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 center dot h/mL (test) and 70,178 +/- 42,560 ng center dot 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 6