Pharmacokinetics and bioequivalence evaluation of two formulations of 10-mg amlodipine besylate: an open-label, single-dose, randomized, two-way crossover study in healthy Chinese male volunteers.

BACKGROUND: Amlodipine is a third-generation dihydropyridine calcium antagonist for the treatment of angina and hypertension. The relative bioavailability of a newly developed dispersible tablet as compared with an established branded formulation has not been reported in a Chinese population.

OBJECTIVE: The aim of this study was to assess and compare the pharmacokinetic properties, bioavailability, and bioequivalence of a newly developed dispersible tablet formulation of amlodipine besylate with those of an established branded formulation in healthy Chinese adult male volunteers.

METHODS: An open-label, single-dose, randomized, 2-way crossover study was conducted in fasted healthy Chinese male volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 2 tablets (5 mg each) of the test or reference formulation, followed by a 2-week washout period and administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Serum samples were collected over 120 hours. Amlodipine concentrations in the serum were analyzed by liquid chromatography tandem mass spectrometry with positive ion electrospray ionization using the multiple reaction monitoring mode. The visible detection of the method was in the range of 0.2 to 32.0 ng/mL, and the lower limit of quantification for amlodipine was 0.2 ng/mL. The amlodipine serum concentration-time curves were used to obtain pharmacokinetic parameters including AUC(0-t), AUC(0-infinity)), and C(max). The criteria for bioequivalence were 90% CIs of 80% to 125% for AUC and 70% to 143% for C(max), according to guidelines of the State Food and Drug Administration of the People's Republic of China. Tolerability was based on the recording of adverse events (AEs), monitoring vital signs, electrocardiograms, and clinical laboratory tests at baseline and completion of the study.

RESULTS: A total of 20 healthy Chinese male volunteers (mean [SD] age, 21.4 [2.6] years [range, 1926 years]; weight, 61.3 [5.4] kg [range, 54.0-75.0 kg]; and height, 171.2 [3.6] cm [range, 162.0-177.0 cm) were included in the study. The mean (SD) C(max), T(max), AUC(0-t), and AUC(0-infinity)) values after administration of the test and reference formulations, respectively, were as follows: 5.46 (1.13) versus 5.88 (1.24) ng/mL, 7.70 (2.08) versus 9.20 (4.18) hours, 284.56 (77.59) versus 311.34 (75.97) ng/mL/h, and 331.37 (111.03) versus 358.74 (101.10) ng/mL/h. The mean (SD) t(1/2) was 38.52 (10.51) hours for the test formulation and 38.75 (7.07) hours for the reference formulation. On analysis of variance, no period or sequence effects were observed for any pharmacokinetic property; however, a significant formulation effect was observed for C(max), AUC(0-t), and AUC(0-infinity)). The relative bioavailability of the test formulation was 90.9% by mean AUC(0-t) and 91.2% by mean AUC(0-infinity). The 90% CIs for the ratios of C(max), AUC(0-t), and AUC(0-infinity) were 88.4% to 97.5%, 86.4% to 95.7%, and 85.8% to 97.0%, respectively, meeting the predetermined criteria for bioequivalence. One subject (5%) reported 2 AEs. The AEs were mild, possibly associated with study drug, and resolved spontaneously by the next evaluation. No serious AEs were reported.

CONCLUSIONS: In this small study in healthy Chinese adult male volunteers, a single 10-mg dose of the dispersible tablet formulation (test) of amlodipine besylate met the regulatory criteria for bioequivalence to the established tablet formulation (reference) based on the rate and extent of absorption. Both formulations were well tolerated.