Almeida Luis, Falcão Amílcar, Vaz-da-Silva Manuel, Nunes Teresa, Santos Ana-Teresa, Rocha José-Francisco, Neta Carla, Macedo Tice, Fontes-Ribeiro C, Soares-da-Silva P
Department of Research & Development, BIAL, S Mamede do Coronado, Portugal.
Eur J Clin Pharmacol. 2008 Oct;64(10):961-6. doi: 10.1007/s00228-008-0534-2. Epub 2008 Aug 6.
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.
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.
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).
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.
奈比卡朋是一种新型儿茶酚-O-甲基转移酶抑制剂。在体外，奈比卡朋已显示出对CYP2C9有抑制作用，而CYP2C9负责S-华法林的代谢。本研究的目的是调查奈比卡朋对健康受试者中华法林药代动力学和药效学的影响。
对16名健康志愿者进行单中心、开放标签、随机、两期交叉研究。在一个时期，受试者每日三次服用200mg奈比卡朋，共9天，并在第4天上午服用奈比卡朋时同时单剂量服用消旋华法林25mg（试验）。在另一个时期，受试者单独单剂量服用消旋华法林25mg（对照）。治疗期之间有14天的洗脱期。
对于R-华法林，试验组的平均±标准差C(max)为1619±284ng/mL，对照组为1649±357ng/mL，而AUC(0-t)分别为92796±18976ng·h/mL（试验）和73597±11363ng·h/mL（对照）。R-华法林试验组与对照组的几何平均比值（GMR）和90%置信区间（90%CI），C(max)为0.973（0.878-1.077），AUC(0-t)为1.247（1.170-1.327）。对于S-华法林，试验组的平均±标准差C(max)为1644±331ng/mL，对照组为1739±392ng/mL，而AUC(0-t)分别为66627±41199ng·h/mL（试验）和70178±42560ng·h/mL（对照）。S-华法林试验组与对照组的GMR和90%CI，C(max)为0.932（0.845-1.028），AUC(0-t)为0.914（0.875-0.954）。药效学参数（国际标准化比值，INR）未发现差异。
奈比卡朋对S-华法林药代动力学或凝血终点（INR）无显著影响。发现对R-华法林代谢有轻度抑制，但不太可能具有临床相关性。
