Bioequivalence study of S-amlodipine Gentisate Conventional Versus new Formulation

기존제형 S-amlodipine gentisate 에 대한 변경제형 S-amlodipine gentisate 의 생물학적동등성 연구

Background: Amlodipine, a dihydropyridine calcium channel blocker, is prescribed for the management of angina and hypertension. It is used therapeutically as a racemic mixture, composed of S- and R-enantiomers. However, its calcium channel blocking activity is confined to S-amlodipine; R-amlodipine has 1000-fold less activity than the S-enantiomer. Objective: The objective of this study was to compare the pharmacokinetic characteristics and safety profiles of the newly developed S-amlodipine formulation, composed of different additives, with those of the previously developed formulation. Methods: This randomized, double blind, two periods, two sequence crossover study was conducted in 24 healthy male volunteers at Seoul National University Hospital Clinical Trials Center. All subjects were randomly assigned to one of two sequence groups: (1) a single dose of the new S-amlodipine formulation (5 mg, 2.5mg/tablet) in the first study period, followed by a single dose of the reference S-amlodipine formulation (5 mg, 2.5mg/tablet) in the second study period, or (2) vice versa. A 14 day-washout separated the study periods. Blood samples for pharmacokinetic analysis of S-amlodipine were collected just before study drug administration and at predefined time points up to 168 hours post dose. Safety profiles including hematology, biochemistry, electrocardiography, and urinalysis were assessed throughout the study. Pharmacokinetics of the two formulations were characterized using noncompartmental model and compared between the formulations. Results: The pharmacokinetic profiles of S-amlodipine were comparable between the formulations. The mean [SD] values for $C_{max}$ in reference and test formulation (3.4 [0.8] ug/L vs 3.3 [0.88] ug/L, respectively) and AUC from time 0 to the last available measurement ($AUC_{last}$) (159.2 [45.6] ug*h/L vs 160.6 [48.9] ug*h/L, respectively) were similar. The calculated 90% confidence interval of the corresponding ratios of log-transformed $C_{max}$ and $AUC_{last}$, were 0.90~1.03 and 0.93~1.08, respectively. Neither formulation caused any serious adverse events. Conclusions: Both formulations were safe and well tolerated in tested dose, 5 mg of S-amlodipine. This study provides evidence for similar pharmacokinetic characteristics of the newly developed formulation of S-amlodipine to a previously prescribed formulation in healthy Korean male volunteers.