Bioequivalence Study of Valsartan/Amlodipine Combination Tablets in Healthy Chinese Volunteers

OBJECTIVE To investigate the bioequivalence of generic formulation of valsartan/amlodipine combination tablets(test) and the original brand Exforge^®(reference). METHODS This study was designed as single-center, randomized, open-label, single-dose, three-period partially repeating crossover. Subjects were randomized to receive a single oral dose of 80/5 mg of test or reference valsartan/amlodipine tablets according to randomized schedule under fasting or fed states. A 2-week washout period was applied. Blood samples were collected up to 72 h following drug administrations. Plasma valsartan and amlodipine concentrations were determined by LC-MS/MS. The pharmacokinetic parameters were calculated with the Phoenix WinNonlin software(version 8.0) based on non-compartmental analysis. Due to high variability, the bioequivalence of valsartan was evaluated using the reference-scaled average bioequivalence(RSABE) and average bioequivalence(ABE) method. The bioequivalence of amlodipine was evaluated by ABE method. RESULTS The within-subject standard deviations(S_WR) of valsartan of the reference product for C_max, AUC_0-t, and AUC_0-∞ under fasting states, and S_WR for C_max during fed were all >0.294, perinitting use of RSABE. The 95% upper confidence limit was <0 for all theses parameters, and the geometric mean ratio(GMR) values of generic/reference product for the point estimates of C_max, AUC_0-t, and AUC_0-∞ were within the range of 80.00%-125.00%. S_WR(valsartan) for AUC_0-t and AUC_0-∞under fed states were all <0.294, permitting use of ABE. The 90% confidence intervals for the GMR of AUC_0-t and AUC_0-∞ of valsartan were within the range of 80.00%-125.00%. In summary, valsartan in the two formulations was bioequivalent. The S_WR(amlodipine) for C_max, AUC_0-t, and AUC_0-∞ were all <0.294, permitting use of ABE. The 90% confidence intervals for the GMR of these parameters were within the range of 80.00%-125.00%, indicating bioequivalence. CONCLUSION The generic formulation of valsartan/amlodipine combination tablets is bioequivalent to the reference marketed brand. Both valsartan/amlodipine formulations were well tolerated.