Confirmation of bioequivalence of the generic fixed combination of amlodipine, hydrochlorothiazide and valsartan (TIARA TRIO®) to the reference medicinal product (EXFORGE HCT®)02 October 2019
Purpose. to prove the bioequivalence (BE) of the test medicinal product (MP) TIARA TRIO®, film-coated tablets, 10 mg amlodipine / 12.5 mg hydrochlorothiazide / 160 mg valsartan, manufactured by PrJSC “Pharmaceutical Firm “Darnitsa” (Ukraine), to the reference MP EXFORGE НСТ®, film-coated tablets, 10 mg amlodipine / 12.5 mg hydrochlorothiazide / 160 mg valsartan, manufactured by Novartis Farmaceutica S.A. (Spain) in a comparative randomized crossover, two-sequence, four-period study (according to the TRTR/RTRT scheme) А. (Spain).
Object and methods of the study. Male and female volunteers administered one tablet of the test and reference MPs once on an empty stomach during each period. In periods I and II, blood samples were taken within 72 hours, in periods III and IV — within 36 hours. The plasma concentrations of amlodipine and hydrochlorothiazide (periods I and II) and valsartan (all periods) were measured using high-performance liquid chromatography with tandem mass-spectrometric detection (HPLC-MS/MS).
Results. Pharmacokinetic analysis included data from 39 healthy volunteers. The mean Сmax values for the test MP TIARA TRIO® and the reference product EXFORGE HCT® were 7.485 ± 1.664 ng/ml and 7.661 ± 1.923 ng/ml (for amlodipine), 78.63 ± 20.97 ng/ml and 78.18 ± 18.27 ng/ml (for hydrochlorothiazide) and 4.85 ± 1.88 μg/ml and 4.94 ± 2.18 μg/ml (for valsartan), respectively. The mean AUC0–72 values of amlodipine, AUC0–t values of hydrochlorothiazide and AUC0–t values of valsartan were respectively 258.454 ± 64.639 ng h/ml, 519.67 ± 130.55 ng h/ml and 31.65 ± 13.90 μg h/ml for the test MP and 261.086 ± 71.287 ng h/ml, 518.22 ± 119.93 ng h/ml and 31.93 ± 15.00 µg h/ml for the reference products. 90% confidence interval limits for ratios of geometric means of Cmax (94.55–101.97% for amlodipine, 94.85–105.42% for hydrochlorothiazide and 90.71–109.72% for valsartan), AUC0–72 (96.82–102.39% for amlodipine) and AUC0–t (95.11–104.54% for hydrochlorothiazide and 92.26–109.27% for valsartan) for Tiara TRIO® and EXFORGE HCT® meet the predefined acceptance criterion for bioequivalence (80.00%–125.00%). Adverse reactions were reported in 8 volunteers after administering the test product and in 8 volunteers after administering the reference product.
Conclusions. The study proved the bioequivalence of the generic medicinal product TIARA TRIO®, film-coated tablets, 10 mg amlodipine / 12.5 mg hydrochlorothiazide / 160 mg valsartan to the reference MP EXFORGE НСТ®, film-coated tablets, 10 mg amlodipine / 12.5 mg hydrochlorothiazide / 160 mg valsartan. Both medicinal products were characterized with comparable tolerability and safety with single oral dosage on an empty stomach.
The sponsor of the study, PrJSC “Pharmaceutical Firm “Darnitsa” expresses its gratitude to the employees of the medical centre INNOPHAR – Ukraine Innovative Pharma Research Clinic Ltd (Ukraine) and the bioanalytical laboratory of QUINTA-ANALYTICA s.r.o. (Czech Republic) for conducting the research and processing its results.