Pharmacokinetic properties and bioequivalence of 2 formulations of valsartan 160-mg tablets: A randomized, single-dose, 2-period crossover study in healthy Korean male volunteers

Abstract

Background: The solubility of valsartan is dependent on pH and thus may cause patient variability in drug absorption and failure in bioequivalence studies; thus, increasing the solubility and release of valsartan at low pH has been suggested for a more favorable pharmacokinetic profile. However, due to this pH dependence, the change in the formulation process could alter the disintegration and/or dissolution profile of the drug, possibly making the results of bioequivalence studies misleading.

Objective: The aim of this study was to assess the bioavailability and tolerability of a newly developed oral formulation of valsartan 160 mg (wet-granulation tablet) in healthy Korean male volunteers.

Method: This study was performed with the subjects under fasted conditions, using a randomized, single-dose, 2-period crossover design. Subjects were assigned to receive, in randomized order, a single dose of the test formulation and a reference formulation (valsartan 160-mg dry-granulation tablet), with a washout period of 7 days between the administrations. Blood samples were collected up to 24 hours after dosing, and pharmacokinetic parameters were determined after the plasma valsartan concentration was analyzed using UPLC-MS/MS. The dissolution studies of both formulations were conducted using USP apparatus 2 at 50 rpm with 1000 mL of phosphate buffer solution (pH, 6.8) at 37°C ± 0.5°C. Bioequivalence was defined per Korean Food and Drug Administration's regulatory criteria as 90% CIs of the geometric mean test/reference ratios of AUC0-t and Cmax within the range of 0.8 to 1.25. Tolerability was assessed using physical examination and subject interviews.

Results: Sixty subjects were enrolled (mean [SD] age [range], 23.6 [2.4] years [21-31]; height, 173.7 [6.6] cm [161-190]; and weight, 68.0 [8.7] kg [54-85]). The mean AUC0-∞ values with the test and reference tablets were 31,784 (13,844) and 32,714 (14,512) ng · h/mL, respectively; Cmax, 5094 (2061) and 5064 (1864) ng/mL; Tmax, 2.92 (1.04) and 3.08 (1.01) hours. The 90% CIs for the geometric mean test/reference ratios of AUC0-t and Cmax were 0.9295 to 1.0546 and 0.9190 to 1.0848, respectively, which met the criteria for bioequivalence. The most frequently reported adverse event was dizziness after blank blood sampling, recorded in 4 subjects, 2 cases each with the test and reference formulations.

Conclusions: In this study in healthy Korean male volunteers, the test and reference formulations of 160-mg valsartan met the Korean Food and Drug Administration's regulatory criteria for bioequivalence despite the difference in formulation (wet granulation vs dry granulation). Both formulations were well tolerated, with no serious adverse events reported.

Keywords: Korean male volunteer; bioequivalence; pharmacokinetic; valsartan; wet granulation.