Bioequivalence of amlodipine, hydrochlorothiazide and valsartan fixed-dose combination generic medicinal product (Tiara Trio^®) to the reference medicinal product Exforge HCT^®: results of a randomized crossover clinical trial in healthy volunteers

The aim is to prove the bioequivalence of the test medicinal product Tiara Trio^®, amlodipine 10 mg/hydrochlorothiazide 12.5 mg/valsartan 160 mg film-coated tablets (PrJSC «Pharmaceutical Firm «Darnitsa», Ukraine) and the reference medicinal product Exforge HCT^®, amlodipine 10 mg/hydrochlorothiazide 12.5 mg/valsartan 160 mg film-coated tablets («Novartis Farmaceutica S. A.», Spain) in a comparative randomized four-period two-sequence (TRTR/RTRT) crossover clinical trial in healthy volunteers. Materials and methods. During each period, male and female volunteers took 1 tabl. of the test or reference medicinal products in the fasting condition. In the I and II periods, blood samples were drawn within 72 hours and they were taken within 36 hours in the III and IV periods. Quantitative determination of amlodipine and hydrochlorothiazide (in periods I and II) and valsartan (in all periods) in blood plasma of the volunteers was performed using high-performance liquid chromatography with tandem mass selective detection. Results. Data from 39 healthy volunteers were included in the analysis of pharmacokinetics. For Tiara Trio^® and Exforge HCT^®, mean C_max values were 7.485±1.664 and 7.661±1.923 ng/mL for amlodipine, 78.63±20.97 and 78.18±18.27 ng/mL for hydrochlorothiazide and 4.85±1.88 and 4.94±2.18 μg/mL for valsartan, respectively. Mean amlodipine AUC_0–72, hydrochlorothiazide AUC_0–t and valsartan AUC_0–t were 258.454±64.639 ng‧h/mL, 519.67±130.55 ng‧h/mL and 31.65±13.90 μg‧h/mL, respectively, for the test medicinal product and 261.086±71.287 ng‧h/mL, 518.22±119.93 ng‧h/mL and 31.93±15.00 μg‧h/mL, respectively, for the reference medicinal product. The ranges of 90% confidence intervals of geometric mean ratio for C_max (94.55–101.97% for amlodipine, 94.85–105.42% for hydrochlorothiazide and 90.71–109.72% for valsartan), AUC_0–72 (96.82–102.39% for amlodipine) and AUC_0–t (95.11–104.54% for hydrochlorothiazide and 92.26–109.27% for valsartan) for Tiara Trio^® and Exforge HCT^® meet prespecified acceptance criteria for bioequivalence (80.00–125.00%). Adverse reactions were reported in 8 volunteers for both test and reference medicinal pro­ducts. Conclusions. The bioequivalence of generic medicinal product Tiara Trio^®, amlodipine 10 mg/hydrochlorothiazide 12.5 mg/valsartan 160 mg film-coated tablets, and the reference medicinal product Exforge HCT^®, amlodipine 10 mg/hydrochlorothiazide 12.5 mg/valsartan 160 mg film-coated tablets, was proven. Both drugs were reported to have comparable tolerability and safety following a single dose oral administration in the fasting state.