Effect of nebicapone on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.
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 x h/mL (test) and 73,597 +/- 11,363 ng x 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 x h/mL (test) and 70,178 +/- 42,560 ng x 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).


CONCLUSIONS
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.
Almeida
Luis
L
Department of Research & Development, BIAL, S Mamede do Coronado, Portugal.
Falcão
Amílcar
A
Vaz-da-Silva
Manuel
M
Nunes
Teresa
T
Santos
Ana-Teresa
AT
Rocha
José-Francisco
JF
Neta
Carla
C
Macedo
Tice
T
Fontes-Ribeiro
C
C
Soares-da-Silva
P
P
D000328:Adult; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects; D065098:Catechol O-Methyltransferase Inhibitors; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008657:Metabolic Clearance Rate; D013237:Stereoisomerism; D013810:Therapeutic Equivalency; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D055815:Young Adult
D000925:Anticoagulants; D065098:Catechol O-Methyltransferase Inhibitors; D014859:Warfarin