Poster Abstract #8: Effect of Nebicapone (BIA 3-202) on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Subjects

• Published in: Neurotherapeutics Vol. 5; no. 3; pp. 492 - 493
• Main Authors: Almeida, Luis, Nunes, Teresa, Vaz-da-Silva, Manuel, Soares-da-Silva, Patricio, Falcão, Amilcar
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.07.2008
• ISSN: 1933-7213; 1878-7479; 1878-7479
• DOI: 10.1016/j.nurt.2008.03.009

Nebicapone (BIA 3-202) is a new catechol- O-methyltransferase (COMT) inhibitor. Warfarin is a racemic mixture of the R- and S-enantiomers, with most of the anticoagulant activity attributable to S-warfarin. In vitro, nebicapone showed an inhibitory effect upon CYP2C9, which is known to be 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 a single-center, open-label, randomized, two-way crossover study in 16 healthy volunteers, two treatment periods were separated by a washout period of 14 days. In one period, subjects received nebicapone 200 mg thrice daily for 9 days, and a warfarin 25 mg single dose concomitantly with the nebicapone morning dose on day 4 (Test). In the other period, a warfarin 25 mg single dose was administered alone (Reference). Regarding S-warfarin, mean C max and AUC 0- t were respectively 1644 ng/mL and 66,627 ng.h/mL after Test, and 1739 ng/mL and 70,178 ng.h/mL after Reference. The S-warfarin Test/Reference geometric mean ratio (GMR) and 90% confidence interval (90%CI) was 0.932 (0.845;1.028) for C max and 0.914 (0.875;0.954) for AUC 0- t . Regarding R-warfarin, mean C max and AUC 0- t were respectively 1619 ng/mL and 92,796 ng.h/mL after Test, and 1649 ng/mL and 73,597 ng.h/mL after Reference. The R-warfarin Test/Reference GMR and 90%CI was 0.973 (0.878;1.077) for C max and 1.247 (1.170;1.327) for AUC 0- t . No differences were found regarding the pharmacodynamic parameter INR. Nebicapone showed no significant effect on the S-warfarin pharmacokinetics or on the coagulation endpoint (INR). A mild inhibition of the R-warfarin metabolism was found, but although the anticoagulant effect of R-warfarin is five times less potent than that of S-warfarin, the reported effect on R-warfarin metabolism is unlikely to be of clinical relevance. Supported by BIAL-Portela & C a SA.