RESUMEN
BACKGROUND: Amlodipine, a dihydropyridine calcium channel antagonist, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers, but its calcium channel-blocking effect is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than its S-enantiomer. OBJECTIVE: The objective of this study was to compare the pharmacokinetic and pharmacodynamic properties and safety profiles of a newly developed amlodipine formulation, composed wholly of S-amlodipine, with those of the conventionally prescribed racemic formulation. METHODS: This randomized, open-label, 2-period, comparative, crossover study was conducted with healthy volunteers at the Gil Medical Center and Gachon Medical School, Incheon, Korea. Male subjects, aged 20 to 50 years, were eligible to participate if their weight was within 20% of ideal body weight and if they were judged by physicians to be healthy. All subjects were randomly assigned in a 1:1 ratio to 1 of 2 treatment sequences: (1) a single dose of the test amlodipine formulation (S-enantiomer amlodipine 5 mg p.o.) (Lodien [Hanlim Pharmaceutical Co., Seoul, Korea]) in the first study period, followed by a single dose of the reference amlodipine formulation (racemate 10 mg p.o.) (Norvasc [Pfizer Pharmaceuticals Korea Ltd., Seoul, Korea]) in the second study period, or (2) a single dose of the reference formulation in the first study period, followed by a single dose of the test formulation in the second period. A 3-week washout occurred between study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration. Pharmacodynamic variables (ie, systolic and diastolic blood pressure and heart rate) were measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24, 48, and 72 hours after administration. Safety profiles were also assessed. Hematology, biochemistry, electrocardiography, and urinalysis were performed at baseline and end of study. Adverse events were monitored throughout the study period. Pharmacokinetic characteristics were compared using noncompartmental analysis. Pharmacokinetic equivalence was concluded if the geometric mean ratios of the plasma Cmax and AUC were within the predetermined range of 80% to 125%. RESULTS: Twenty-six healthy Korean male volunteers were screened and 18 subjects (mean [SD] age, 23.4 [1.5] years [range, 21-26 years]; mean [SD] weight, 69.3 [6.8] kg [range, 60-88 kg]) were enrolled and completed the study. The plasma concentration-time profiles of S-amlodipine were comparable after administration of both formulations. The mean (SD) values for Cmax AUC from time 0 to the last available measurement (AUC(last)), and AUC from 0 to infinity (AUC(0-infinity)) for the reference formulation (3.0 [0.6] ng/mL, 151.4 [35.7] ng x h/mL, and 175.3 [45.1] ng x h/mL, respectively) did not differ significantly from those for the test formulation (3.1 [0.6] ng/mL, 139.7 [40.3] ng x h/mL, and 161.7 [43.8] ng x h/mL, respectively). The calculated 90% Cls for the corresponding ratios of log-transformed Cmax, AUCO(0-infinity), and AUC(last) were 97.56% to 112.51%, 86.31% to 98.74%, and 83.46% to 100.04%, respectively, which met the predetermined criteria for pharmacokinetic equivalence. Despite the single administration, significant changes in maximal blood pressure and heart rate were observed after drug administration for both formulations, compared with baseline values (all, P < 0.001). However, no significant differences were observed between the 2 formulations in terms of pharmacodynamic profiles, and no clinically relevant changes were observed for either formulation with respect to physical examination, hematology, biochemistry, electrocardiography, or urinalysis. Neither formulation caused any serious adverse events. CONCLUSIONS: Two amlodipine formulations were found to be equivalent in terms of the pharmacokinetics of S-amlodipine. The newly developed formulation, comprised of only S-amlodipine, had pharmacodynamic profiles comparable to those of the conventional racemic amlodipine formulation in these healthy Korean male subjects. Both formulations were well tolerated.