Bioequivalence of a generic medicinal product Tiara Duo (valsartan and hydrochlorothiazide fixed-dose combination) to the reference medicinal product Co-Diovan®: results of a randomized crossover clinical trial in healthy volunteers

September 23, 2019
796
Resume

The aim is to prove the bioequivalence of the test medicinal product Tiara Duo, 160 mg valsartan/25 mg hydrochlorothiazide film-coated tablets (PrJSC «Pharmaceutical Firm «Darnitsa», Ukraine), and the reference medicinal product Co-Diovan®, 160 mg valsartan/25 mg hydrochlorothiazide film-coated tablets («Novartis Pharmaceuticals UK LTD», United Kingdom) in a comparative randomized four-period two-sequence (TRTR/RTRT) crossover clinical trial in healthy volunteers. Materials and methods. During each period, male volunteers took 1 tabl. of the test or reference medicinal product in the fasting condition. Blood samples were taken within 36 hours. Quantitative determination of valsartan and hydrochlorothiazide in blood plasma was performed using ultra-performance liquid chromatography with tandem mass-selective detection. Results. Data from 34 healthy volunteers were included in the analysis of pharmacokinetics. For Tiara Duo and Co-Diovan®, mean Cmax values were 3460.6±1580.9 and 3293.5±1717.9 ng/mL (for valsartan) and 158.16±92.50 and 162.40±94.09 ng/mL (for hydrochlorothiazide), respectively. Mean valsartan and hydrochlorothiazide AUC0–t values were 19508.75±9079.00 and 1095.55±655.50 ng‧h/mL for the test medicinal product and 18175.84±9537.15 and 1115.35±666.47 ng‧h/mL, for the reference medicinal product, respectively. The ranges of 90% confidence intervals of geometric mean ratio for Cmax (97.33–123.22% for valsartan and 91.78–104.74% for hydrochlorothiazide) and AUC0–t (100.25–122.52% for valsartan and 92.68–103.83% for hydrochlorothiazide) for Tiara Duo and Co-Diovan® meet prespecified acceptance criteria for bioequivalence (80.00–125.00%). Suspected adverse reactions were reported in 2 vo­lunteers and were considered to be non-serious. Conclusions. The bioequivalence of generic medicinal product Tiara Duo, 160 mg valsartan/25 mg hydrochlorothiazide film-coated tablets, and the reference medicinal product Co-Diovan®, 160 mg valsartan/25 mg hydrochlorothiazide 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: 23.09.2019

References:

  • Ambrosioni E. (2001) Healthcare benefits of very-low-dose combination treatment in the management of hypertension. J. Hypertens., 19: S29–S36.
  • Benz J.R., Black H.R., Graff A. et al. (1998) Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo-controlled trial comparing combination therapy with monotherapy. J. Hum. Hypertens., 12: 861–866.
  • 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.
  • Chrysant S.G., Wombolt D.G., Feliciano N. et al. (1998) Long-term efficacy, safety, and tolerability of valsartan and hydrochlorothiazide in patients with essential hypertension. Curr. Ther. Res., 59: 762–772.
  • Collins R., Peto R., MacMahon S. et al. (1990) Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet, 335: 827–838.
  • EMA (2010) Guideline on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98/Rev.1/Corr (https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf).
  • EMA (2015) Guideline on bioanalytical method validation. EMEA/CHMP/192217/2009 Rev. 1 Corr 2 (https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf).
  • EMA (2016) Guideline for good clinical practice E6(R2). EMA/CHMP/ICH/135/199 (https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r1-guideline-good-clinical-practice-step-5_en.pdf).
  • 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 (http://ec.europa.eu/health/files/eudralex/vol-10/ctqa_v11.pdf, http://ec.europa.eu/health/files/clinicaltrials/2012_07/summary/2012_07_summary_en.pdf).
  • 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.
  • Hajjar I., Kotchen T.A. (2003) Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA, 290: 199–206.
  • Hall J., Marbury T., Gray J. et al. (1998) Long term safety, tolerability and efficacy of valsartan: results from one and two year trials. J. Drug Assess, 1: 281–293.
  • Hall W.D., Montoro R., Littlejohn T. et al. (1998) Efficacy and tolerability of valsartan in combination with hydrochlorothiazide in essential hypertension. Clin. Drug. Invest., 16: 203–210.
  • Hansson L., Zanchetti A., Carruthers S.G. et al. (1998) Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet, 351: 1755–1762.
  • ICH (2016) Integrated addendum to ICH E6(R1): Guideline for good clinical practice E6(R2) (https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdf).
  • 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.
  • Lacourciere Y., Poirier L., Hebert D. et al. (2005) Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, double-blind, parallel-group trial. Clin. Ther., 27: 1013–1021.
  • Lacourciere Y., Wright J. Jr., Samuel R. et al. (2009) Effects of force-titrated valsartan/hydrochlorothiazide versus amlodipine/hydrochlorothiazide on ambulatory blood pressure in patients with stage 2 hypertension: the EVALUATE study. Blood Press. Monit., 14: 112–120.
  • 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.
  • Mallion J.-M., Carretta R., Trenkwalder P. et al. (2003) Valsartan/hydrochlorothiazide is effective in hypertensive patients inadequately controlled by valsartan monotherapy. Blood Press., 12(Suppl. 1): 36–43.
  • Meredith P.A. (2005) Angiotensin II receptor antagonists alone and combined with hydrochlorothiazide: potential benefits beyond the antihypertensive effect. Am. J. Cardiovasc. Drug, 5: 171–183.
  • 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).
  • Scholze J., Probst G., Bertsch K. (2000) Valsartan alone and in combination with hydrochlorothiazide in general practice: results from two postmarketing surveillance studies involving 54 928 patients with essential hypertension. Clin. Drug Invest., 20: 1–7.
  • Sowers J., Raij L., Jialal I. et al. (2010) Angiotensin receptor blocker/diuretic combination preserves insulin responses in obese hypertensives. J. Hypertens., 28: 1761–1769.
  • WHO TRS N 937 (2006) Additional guidance for organization performing in vivo bioequivalence studies. Annex 9.
  • Williams B., Mancia G., Spiering W. et al. (2018) 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur. Heart. J., 39(33): 3021–3104.
  • Zappe D., Palmer B., Calhoun D. et al. (2010) Effectiveness of initiating treatment with valsartan/hydrochlorothiazide in patients with stage 1 or stage 2 hypertension. J. Hum. Hyperten., 24: 483–491.
  • Verkhovna Rada Ukrainy (1996) Zakon Ukrainy vid 04.04.1996 r. «Pro likarski zasoby» (https://zakon.rada.gov.ua/laws/show/123/96-%D0%B2%D1%80).
  • Vsemirnaya meditsinskaya assotsiatsiya (1964) Helsinkskaya 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. 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» (https://zakon.rada.gov.ua/laws/show/z1069-05).
  • 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» (https://zakon.rada.gov.ua/laws/show/z1010-09).
  • 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 42-7.1:2014 (2014) Nastanova «Likarski zasoby. Doslidzhennia bioekvivalentnosti». Zatverdzheno nakazom MOZ Ukrainy vid 13.06.2014 r. № 396.
  • 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.