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Bioequivalence of a medicinal product PERINDOPRES A (perindopril and amlodipine fixed-dose combination) to the original medicinal product Bi-PRESTARIUM®: the results of a randomized crossover clinical trial in healthy volunteers

March 3, 2020
914
Cardiology, Rheumatology
Therapy, General practice
Kravchuk Zh.
Kuznetsov I.E.
Kubeš V.
Tsapko G.V.
Sotnychenko N.M.
Doroshenko A.
Keywords :
amlodipine,
bioequivalence,
generic,
healthy volunteers,
perindipril,
reference drug,
tablets
Specialities :
Cardiology, Rheumatology
Therapy, General practice
Resume

The aim was to prove the bioequivalence of the test medicinal product PERINDOPRES A, 8 mg perindopril tert-butylamine/10 mg amlodipine tablets, manufactured by PrJSC «Pharmaceutical Firm «Darnitsa» (Ukraine) and the reference medicinal product Bi-PRESTARIUM®, 10 mg perindipril arginine/10 mg amlodipine tablets, manufactured by Servier (Ireland) Industries Ltd (Ireland) in a comparative randomized two-period two-sequence (TR/RT) crossover clinical trial in healthy volunteers. Materials and methods. During each period, male and female volunteers took 1 tablet of the test or reference medicinal products in the fasting condition. Blood samples were taken within 72 hours. Quantitative determination of perindopril and amlodi­pine in blood plasma of the volunteers was performed using high-performance liquid chromatography with tandem mass spectrometric detection. Results. Data from 42 or 41 healthy volunteers were included in pharmacokinetics analysis of perindopril and amlodipine, respectively. For perindopril and amlodipine, corresponding mean Cmax values were 89.43±29.17 and 5.798±1.430 ng/mL for the test medicinal product PERINDOPRES A and 91.02±26.05 and 5.748±1.386 ng/mL for the reference medicinal product Bi-PRESTARIUM®. Mean perindopril AUC0–t and mean amlodipine AUC0–72 values were 97.67±30.95 and 219.293±65.274 ng‧h/mL, respectively, after a single dose of test medicinal product and 102.74±31.98 and 215.675±61.202 ng‧h/mL, respectively, after a single dose of reference medicinal product. Ranges of 90% confidence intervals of PERINDOPRES A/Bi-PRESTARIUM® geometric mean ratios for Cmax (91.80–103.13% for perindopril and 96.43–104.86% for amlodipine), AUC0–t for perindopril (92.09–97.85%), and AUC0–72 for amlodipine (98.28–103.99%) meet prespecified acceptance criterion for bioequivalence (80.00–125.00%). Ranges of 90% confidence intervals of test/reference geometric mean ratios for Cmax (92.66–103.07%) and AUC0–72 (94.91–99.85%) of perindoprilat (an active metabolite of perindopril) also meet the criterion and additionally support the bioequivalence. Conclusions. The bioequivalence of generic medicinal product PERINDOPRES A, 8 mg perindopril tert-butylamine/10 mg amlodipine tablets, and reference medicinal product Bi-PRESTARIUM®, 10 mg perindopril arginine/10 mg amlodi­pine tablets, was proven according to the up-to-date regulatory standards.

Published: 03.03.2020

 

References:

  • Verkhovna Rada Ukrainy (1996) Zakon Ukrainy vid 04.04.1996 r. «Pro likarski zasoby» (u potochnii redaktsii) (https://zakon.rada.gov.ua/laws/show/123/96-%D0%B2%D1%80).
  • Zhukova N.A., Libina V.V., Kudris I.V., Padalko N.N. (2013) Validatsiya bioanaliticheskogo metoda. Metod. rekomend. 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) (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» (u potochnii redaktsii) (https://zakon.rada.gov.ua/laws/show/z1010-09).
  • MOZ Ukrainy (2019) Nakaz MOZ Ukrainy vid 21.01.2019 r. № 146 «Pro provedennia klinichnykh vyprobuvan likarskykh zasobiv ta zatverdzhennia suttievykh popravok» (https://moz.gov.ua/article/ministry-mandates/nakaz-moz-ukraini-vid-21012019-146-pro-provedennja-klinichnih-viprobuvan-likarskih-zasobiv-ta-zatverdzhennja-suttevih-popravok).
  • Sirenko Yu.M., Lutai M.I., Nesukai O.H. ta in. (2017) Kontrol arterialnoi hipertenzii v Ukraini: vysnovky ekspertiv. Zdorovia Ukrainy, 421: 5–7.
  • ST-N MOZU 42-7.0:2008 (2009) Nastanova «Likarski zasoby. Nalezhna klinichna praktyka». Kyiv, 48 s.
  • ST-N MOZU 42-7.2:2018 (2018) Nastanova «Likarski zasoby. Doslidzhennia bioekvivalentnosti». Zatverdzheno nakazom MOZ Ukrainy № 2014 vid 02.11.2018 r.
  • Canbakan B. (2013) Rational approaches to the treatment of hypertension: drug therapy-monotherapy, combination, or fixed-dose combination? Kidney Int. Suppl. (2011), 3(4): 349–351.
  • 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.
  • Elliott W.J., Whitmore J., Feldstein J.D. et al. (2015) Efficacy and safety of perindopril arginine + amlodipine in hypertension. J. Am. Soc. Hypertens., 9(4): 266–274.
  • 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-r2-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).
  • Fleig S.V., Weger B., Haller H., Limbourg F.P. (2018) Effectiveness of a fixed-dose, single-pill combination of perindopril and amlodipine in patients with hypertension: a non-interventional study. Adv. Ther., 35(3): 353–366.
  • Gradman A.H., Basile J.N., Carter B.L. et al. (2011) Combination the­rapy in hypertension. J. Clin. Hypertens., 13(3): 146–154.
  • Guerrero-García C., Rubio-Guerra A.F. (2018) Combination therapy in the treatment of hypertension. Drugs Context., 7: 212531.
  • 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).
  • Laurent S., Parati G., Chazova I. et al. (2015) Randomized evaluation of a novel, fixed-dose combination of perindopril 3.5 mg/amlodipine 2.5 mg as a first-step treatment in hypertension. J. Hypertens., 33(3): 653–662.
  • Liakos C.I., Papadopoulos D.P., Kotsis V.T. (2017) Adherence to treatment, safety, tolerance, and effectiveness of Perindopril/Amlodipine fixed-dose combination in Greek patients with hypertension and stable coronary artery disease: A pan-hellenic prospective observational study of daily clinical practice. Am. J. Cardiovasc. Drugs, 17(5): 391–398.
  • 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.
  • Neutel J.M., Smith D.H.G. (2013) Hypertension management: rationale for triple therapy based on mechanisms of action. Cardiovasc. Ther., 31(5): 251–258.
  • OECD (2004) The OECD principles of good laboratory practice (GLP).
  • Oparil S., Acelajado M.C., Bakris G.L. et al. (2018) Hypertension. Nat. Rev. Dis. Primers., 4: 18014.
  • Papathanasiou G., Zerva E., Zacharis I. et al. (2015) Association of high blood pressure with body mass index, smoking and physical activity in healthy young adults. Open. Cardiovasc. Med. J., 9: 5–17.
  • Reid J.L., Lees K.R., Perret L. (1987) Perindopril, a new angiotensin converting enzyme inhibitor—Clinical pharmacological studies in healthy subjects. Clinical and experimental hypertension. Part A: Theory and Practice, 9(2–3): 361–364.
  • Shirley M., McCormack P.L. (2015) Perindopril/amlodipine (Prestalia(®)): a review in hypertension. Am. J. Cardiovasc. Drugs., 15: 363–370.
  • Telejko E. (2007) Perindopril arginine: benefits of a new salt of the ACE inhibitor perindopril. Curr Med Res Opin., 23(5): 953–960.
  • WHO TRS N 996 (2016) Guidance for organizations 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.

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