Abstract: AIM: To investigate the pharmacokinetics of ivabradine at single doses or multiple doses in Chinese healthy volunteers. METHODS: This open, random and doubled 3×3 latin clinical trial involved 12 healthy volunteers, who received three single doses and then multiple doses. The concentration of ivabradine and its active metabolite S-18982 in plasma were measured by liquid chromatography/tandem mass spectrometry and the pharmacokinetic parameters were calculated using WinNonlin program. RESULTS: The main pharmacokinetic parameters of ivabradine after single doses(5,10,15 mg)were as follows: C_maxwere(19±10),(47±24),(79±41) μg/L, respectively; t_max were(0.7±0.5),(0.6±0.3),(0.5±0.1) h, respectively; AUC_last were (58±32),(138±83),(189±115) μg·h·L^-1,respectively; AUC_inf were (59±32), (140±84), (191±116) μg·h·L^-1,respectively. The main pharmacokinetic parameters of S-18982 after single doses(5,10,15 mg)were as follows: t_max were (3.1±1.2),(7.9±2.8),(15.0±5.4) μg/L ,respectively; t_max were(1.1±0.8),(0.8±0.4),(0.6±0.1)h, respectively; AUC_last were (17±8), (47±19), (76±29) μg·h·L^-1,respectively; AUC_inf were (20±8),(52±21),(85±30) μg·h·L^-1, respectively. The parameters(C_max, t_max, AUC_last, AUC_inf )of ivabradine after multiple doses(5 mg)were(20±7) μg/L,(1.0±0.7)h, ( 67±32) μg·h·L^-1, (69±33) μg·h·L^-1,respectively; The parameters(C_max, t_max, AUC_last, AUC_inf )of S-18982 after multiple doses(5 mg)were:(4.5±1.3) μg/L,(1.1±0.8) h, (34±11) μg·h·L^-1,(39±13) μg·h·L^-1,respectively.CONCLUSION: After 5-15 mg single doses administration, the pharmacokinetic results show that ivabradine exhibits first order kinetic characteristics, but S-18982 is nonlinear. After 5 mg multiple doses administration, ivabradine and S-18982 reach stable state on day 5, and ivabradine shows no accumulation, but S-18982 exists accumulation phenomenon.

Key words: Ivabradine, Liquid chromatography/tandem mass spectrometry, Pharmacokinetics