Randomized, open-label, two-period crossover comparison of the pharmacokinetic and pharmacodynamic properties of two amlodipine formulations in healthy adult male Korean subjects

Abstract

Background: Amlodipine, a third-generation dihydropyridine calcium antagonist, is prescribed in the management of angina and hypertension. A newly developed amlodipine formulation (amlodipine camsylate) is associated with similar physical properties, melting point, and solubility—and improved stability against long-term stability test and accelerated temperature test—compared with the conventional formulation (amlodipine besylate). Objective: This study was performed to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of a newly developed amlodipine formulation with a conventional formulation in healthy male subjects. Methods: This randomized, open-label, 2-period crossover comparative study was conducted at the Clinical Trial Center, Gil Medical Center, Gachon Medical School (Incheon, Korea). Eighteen healthy male Korean subjects aged 20 to 40 years were enrolled. All subjects received a single oral dose (5-mg tablet) of a conventional (reference) or newly developed (test) amlodipine formulation. Blood samples for PK analysis of amlodipine were obtained during the 144-hour period after dosing. Systolic and diastolic blood pressure (BP) (SBP and DBP, respectively) and pulse rate (PR) were measured just before each blood sampling. Assessment of safety profiles, including hematology and biochemistry, electrocardiography, urinalysis, and monitoring of adverse events (AEs), was performed. Results: All participants completed both treatment periods. Their mean (SD) age was 22.3 (1.5) years (range, 20–25 years) and their mean (SD) body weight was 67.9 (5.6) kg (range, 57–77 kg). The plasma concentration-time profiles of amlodipine were similar after administration of the 2 formulations. The reference and test formulations were pharmacokinetically equivalent. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration and the area under the plasma concentration-time curve were within the predetermined equivalence range of 80% to 125%. Despite administration of a single dose, significant maximal changes in SBP, DBP, and PR were achieved after drug administration for both formulations compared with baseline values (all, P < 0.001). No significant differences in PD profiles were found between the 2 formulations. No clinically relevant changes were observed in physical, biochemical, hematologic, electrocardiographic, or urinalysis findings during the study. Neither formulation caused any AEs during the study. Conclusions: The 2 amlodipine formulations were pharmacokinetically equivalent and showed similar PD characteristics in these healthy male subjects.