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

September 3, 2019

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 Cmax 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 AUC0–72, hydrochlorothiazide AUC0–t and valsartan AUC0–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 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 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.

Published: 03.09.2019

  • Verkhovna Rada Ukrainy (1996) Zakon Ukrainy vid04.1996 r. «Pro likarski zasoby» (u potochnii redaktsii) (
  • Vsemirnaya meditsinskaya assotsiatsiya (1964) Helsinskaya deklaratsiya Vsemirnoy meditsinskoy assotsiatsii. Eticheskie printsipyi dlya meditsinskih issledovaniy s privlecheniem cheloveka v kachestve sub’ekta ispyitaniya (s izmeneniyami).
  • Zhukova N.A., Libina V.V., Kudris I.V., Padalko N.N. (2013) Validatsiya bioanaliticheskogo metoda: Metod. rekomendatsii. GETs MZ Ukrainyi, Kiev, 35 s.
  • MOZ Ukrainy (2005) Nakaz MOZ Ukrainy vid 26.08.2005 r. № 426 «Pro zatverdzhennia Poriadku provedennia ekspertyzy reiestratsiinykh materialiv na likarski zasoby, shcho podaiutsia na derzhavnu reiestratsiiu (perereiestratsiiu), a takozh ekspertyzy materialiv pro vnesennia zmin do reiestratsiinykh materialiv protiahom dii reiestratsiinoho posvidchennia» (u potochnii redaktsii) (
  • MOZ Ukrainy (2009) Nakaz MOZ Ukrainy vid 23.09.2009 r. № 690 «Pro zatverdzhennia Poriadku provedennia klinichnykh vyprobuvan likarskykh zasobiv ta ekspertyzy materialiv klinichnykh vyprobuvan i Typovoho polozhennia pro komisii z pytan etyky» (u potochnii redaktsii) (
  • ST-N MOZU 42-6.0:2008 (2009) Nastanova «Likarski zasoby. Nalezhna laboratorna praktyka». Kyiv, 48 s.
  • ST-N MOZU 42-7.0:2008 (2009) Nastanova «Likarski zasoby. Nalezhna klinichna praktyka». Kyiv, 48 s.
  • ST-N MOZU 42-7.1:2016 (2017) Nastanova «Likarski zasoby. Doslidzhennia bioekvivalentnosti». Zatverdzheno nakazom MOZ Ukrainy vid 12.01.2017 r. № 22.
  • ST-N MOZU 42-7.2:2018 (2018) Nastanova «Likarski zasoby. Doslidzhennia bioekvivalentnosti». Zatverdzheno nakazom MOZ Ukrainy vid 02.11.2018 r. № 2014.
  • Terenda N.O. (2015) Smertnist vid sertsevo-sudynnykh zakhvoriuvan yak derzhavna problema. Visn. nauk. doslidzh., 4: 11–13.
  • Calhoun D.A., Crikelair N.A., Yen J., Glazer R.D. (2009а) Amlodipine/valsartan/hydrochlorothiazide triple combination therapy in moderate/severe hypertension: Secondary analyses evaluating efficacy and safety. Adv. Ther., 26(11): 1012–1023.
  • Calhoun D.A., Lacourcière Y., Chiang Y.T., Glazer R.D. (2009б) Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide. A randomized clinical trial. Hypertension, 54(1): 32–39.
  • Calhoun D.A., Lacourcière Y., Crikelair N.A. et al. (2013) Effects of demographics on the antihypertensive efficacy of triple therapy with amlodipine, valsartan, and hydrochlorothiazide for moderate to severe hypertension. Curr. Med. Res. Opin., 29(8): 901–910.
  • Chow C.K., Teo K.K., Rangarajan S. et al. (2013) Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA, 310(9): 959–968.
  • EMA (2010) Guideline on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98/Rev.1/Corr (
  • EMA (2015) Guideline on bioanalytical method validation. EMEA/CHMP/192217/2009 Rev. 1 Corr 2 (
  • EMA (2016) Guideline for good clinical practice E6(R2). EMA/CHMP/ICH/135/199 (
  • European Commission (2013) Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (,
  • Fogari R., Zoppi A., Mugellini A. et al. (2012) Effects of valsartan versus olmesartan addition to amlodipine/hydrochlorothiazide combination in treating stage 2 hypertensive patients. Expert Opin. Pharmacother., 13(5): 629–636.
  • Gu Q., Burt V.L., Dillon C.F. et al. (2012) Trends in antihypertensive medication use and blood pressure control among United States adults With hypertension. The National Health and Nutrition Examination Survey, 2001 to 2010. Circulation, 126(17): 2105–2114.
  • Hagendorff A., Kurz I., Müller A., Klebs S. (2014) Evaluation of effectiveness and safety of amlodipine/valsartan/hydrochlorothiazide single-pill combination therapy in hypertensive patients: An observational study. J. Drug Assess, 3(1): 1–9.
  • ICH (2016) Integrated addendum to ICH E6(R1): Guideline for good clinical practice E6(R2) (
  • James P., Oparil S., Carter B. et al. (2014) Evidence-based guideline for the management of high blood pressure in adults report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA, 311(5): 507–520.
  • Kizilirmak P., Berktaş M., Uresin Y., Yildiz O.B. (2013) The efficacy and safety of triple vs dual combination of angiotensin II receptor blocker and calcium channel blocker and diuretic: a systematic review and meta-analysis. J. Clin. Hypertens. Greenwich, 15(3): 193–200.
  • Mallat S.G., Itani H.S., Tanios B.Y. (2013) Current perspectives on combination therapy in the management of hypertension. Integr. Blood Press. Control, 6: 69–78.
  • NCD Risk Factor Collaboration (2017) Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants. Lancet, 389: 37–55.
  • OECD (2004) The OECD principles of good laboratory practice (GLP).
  • Sison J., Assaad-Khalil S.H., Najem R. et al. (2014) Real-world clinical experience of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide in hypertension: The EXCITE study. Curr. Med. Res. Opin., 30(10): 1937–1945.
  • WHO TRS N 937 (2006) Additional guidance for organization performing in vivo bioequivalence studies. Annex 9.