COMPARATIVE BIOAVAILABILITY (BIOEQUIVALENCE) STUDY FOR FIXED DOSE COMBINATION TABLET CONTAINING AMLODIPINE, VALSARTAN, AND HYDROCHLOROTHIAZIDE USING A NEWLY DEVELOPED HPLC-MS/MS METHOD

摘要

Objective: The aim of the study was to evaluate the bioequivalence between a newly developed generic tablet containing fixed-dose combination of amlodipine besylate, valsartan and hydrochlorothiazide (10/160/25 mg), and the reference brand product Exforge HCT ? tablet; using a newly developed HPLC-MS/MS method for simultaneous determination of these drugs in human plasma. Methods: The brand (reference) and the test (generic) products were administered to thirty-nine healthy subjects. A fasting, laboratory blind, single-dose, two-treatment, two-period, two-sequence, randomized crossover design was conducted with 14 d washout period between dosing. Serial blood samples were withdrawn from each subject immediately before dosing (zero time), and then at 0.33, 0.66, 1.0, 1.33, 1.66, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 14, 16, 24, 48 and eventually at 72 h post dosing. Plasma samples were analyzed for simultaneous determination of amlodipine, valsartan and hydrochlorothiazide by a newly developed HPLC coupled with MS/MS detector. The linearity of the method was established for plasma concentration ranges of 0.2-12 ng/ml, 50-8000 ng/ml, and 2-250 ng/ml for amlodipine, valsartan, and hydrochlorothiazide, respectively. Results: Plasma concentration-time data of each individual were analyzed by non-compartmental method to measure the pharmacokinetics parameters; C max , T max , AUC 0-t, AUC 0- ￥ , l Z , T 1/2 . For amlodipine truncated AUC 72hr was calculated. The 90% confidence interval for the pharmacokinetic parameters used for bioequivalence evaluation (C max and AUC) for amlodipine, valsartan, and hydrochlorothiazide were well within FDA acceptable ranges of 80-125%. Conclusion: It is concluded that the newly devolved generic product is bioequivalent with the brand product Exforge HCT ? tablet . Thus, both products are clinically interchangeable. Keywords: Amlodipine, Valsartan, Hydrochlorothiazide, Pharmacokinetics, Bioequivalence, HPLC-MS/MS