Confirmation of bioequivalence of Nebivolol-Darnitsa, tablets, and Nebilet®, tablets: results of a randomized crossover clinical trial in healthy volunteers | Ukrainian Medical Journal

Artysh B.,Doroshenko A.,Sontikhenko N.M.,Kubeš V.

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Confirmation of bioequivalence of Nebivolol-Darnitsa, tablets, and Nebilet®, tablets: results of a randomized crossover clinical trial in healthy volunteers

Confirmation of bioequivalence of Nebivolol-Darnitsa, tablets, and Nebilet®, tablets: results of a randomized crossover clinical trial in healthy volunteers

March 7, 2019

1021

Cardiology, Rheumatology

Therapy, General practice

Specialities :

Cardiology, Rheumatology

Therapy, General practice

Resume

The aim is to prove the bioequivalence of the test product Nebivolol-Darnitsa 5 mg tablets of nebivolol, manufactured by PJSC «Pharmaceutical Firm «Darnitsa» (Ukraine), and the reference product Nebilet® 5 mg tablets of nebivolol, manufactured by Berlin-Chemi AG (Germany), in a comparative randomized two-period two-sequence (TR/RT) crossover clinical trial in healthy volunteers. Materials and methods. Volunteers of both sexes took in the fasting condition a single 5 mg nebivolol dose of the test and reference drugs. Blood samples were taken within 48 hours. Quantitative determination of nebivolol in blood plasma of the volunteers was performed using high performance liquid chromatography with tandem mass selective detection. Results. Data from 40 healthy volunteers were included in the analysis of pharmacokinetics. For Nebivolol-Darnitsa and Nebilet®, mean nebivolol C_max values were 2.282±1.961 and 2.228±1.993 ng/ml, respectively, and corresponding mean AUC0_–t values were 26.954±50.678 and 27.745±52.206 ng‧h/mL, respectively. The ranges of 90% confidence intervals of geometric mean ratio for C_max (95.37–110.30%) and AUC0_–t (92.70–102.75%) for Nebololol-Darnitsa and Nebilet® meet prespecified acceptance criteria (80.00–125.00%). Suspected adverse reactions/events were observed in 2 volunteers and were considered to be non-serious. Conclusions. The bioequivalence of Nebivolol-Darnitsa, 5 mg tablets, and the reference product Nebilet®, 5 mg tablets, was proven in accirdance with the guidelines on bioequivalence testing (СТ-Н МОЗУ 42-7.2:2018). Both drugs were well-tolerated following a single dose oral administration in the fasting state.

Published: 07.03.2019

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).
Vsemirnaya meditsinskaya assotsiatsiya (1964) Helsinkskaya deklaratsiya Vsemirnoy meditsinskoy assotsiatsii. Eticheskie printsipyi dlya meditsinskih issledovaniy s privlecheniem cheloveka v kachestve sub’ekta (s izmeneniyami) (http://uacm.kharkov.ua/download/2014_11/22.pdf).
Dolzhenko M.M., Davydova I.V., Shershneva O.V. (2018) Yevropeiski rekomendatsii z vedennia khvorykh na arterialnu hipertenziiu 2018: fokus na ishemichnu khvorobu sertsia. Medychna hazeta «Zdorovia Ukrainy 21 storichchia», 15–16(436–437): 35–36.
Zhukova N.A., Libina V.V., Kudris I.V., Padalko N.N. (2013) Validatsiya bioanaliticheskogo metoda: Metod. rekomendatsii. GETs MZ Ukrainyi, Kiev, 35.
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://zakon2.rada.gov.ua/laws/show/z1069-05).
MOZ Ukrainy (2009a) 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://zakon1.rada.gov.ua/laws/show/z1010-09).
MOZ Ukrainy (2009b) Nakaz MOZ Ukrainy vid 16.02.2009 r. № 95 «Pro zatverdzhennia dokumentiv z pytan zabezpechennia yakosti likarskykh zasobiv» (u potochnii redaktsii) (https://zakon5.rada.gov.ua/rada/show/v0095282-09).
MOZ Ukrainy (2014) Nakaz MOZ Ukrainy vid 02.11.2018 r. № 2014 «Pro vnesennia zmin do nastanovy «Likarski zasoby. Doslidzhennia bioekvivalentnosti» (http://moz.gov.ua/article/ministry-mandates/nakaz-moz-ukraini-vid-02112018–2014-pro-vnesennja-zmin-do-nastanovi-likarski-zasobi-doslidzhennja-bioekvivalentnosti).
MOZ Ukrainy (2017) Nakaz MOZ Ukrainy vid 25.09.2017 r. № 1167 «Pro provedennia klinichnykh vyprobuvan likarskykh zasobiv ta zatverdzhennia suttievykh popravok» (http://old.moz.gov.ua/ua/portal/dn_20170925_1167.html).
Sirenko Yu.M., Lutai M.I., Nesukai O.H. ta in. (2017) Kontrol arterialnoi hipertenzii v Ukraini: vysnovky ekspertiv. Medychna hazeta «Zdorovia Ukrainy 21 storichchia», 24(421): 5–7.
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.
Cicero A.F.G., Kuwabara M., Borghi C. (2018) A critical review of nebivolol and its fixed-dose combinations in the treatment of hypertension. Drugs, 78(17): 1783–1790.
Europese Commissie (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).
European Medicines Agency (2010) Guideline on the investigation of bioequivalence (https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf).
EMA (2015) Guideline on bioanalytical method validation (https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf).
ICH (1997) ICH Topic E 6. Guideline for Good Clinical Practice (https://docplayer.net/6804865-Ich-topic-e-6-guideline-for-good-clinical-practice-note-for-guidance-on-good-clinical-practice-cpmp-ich-135-95.html).
OECD (2004) The OECD principles of good laboratory practice (GLP) (http://www.oecd.org/chemicalsafety/testing/oecdseriesonprinciplesofgoodlaboratorypracticeglpandcompliancemonitoring.htm).
Therapeutic Goods Administration (2000) Note for guidance on good clinical practice (CPMP/ICH/135/95) (https://www.tga.gov.au/sites/default/files/ich13595an.pdf).
Fongemie J., Felix-Getzik E. (2015) A review of nebivolol pharmacology and clinical evidence. Drugs, 75(12): 1349–1371.
Marketou M., Gupta Y., Jain S., Vardas P. (2017). Differential metabolic effects of beta-blockers: an updated systematic review of nebivolol. Current Hypertension Reports, 19(3): 22.
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.
Sharp R.P., Gales B.J. (2017) Nebivolol versus other beta blockers in patients with hypertension and erectile dysfunction. Ther. Adv. Urol., 9(2): 59–63.
Vieira C.P., Neves D.V., Cesarino E.J. et al. (2017) An indirect stereoselective analysis of nebivolol glucuronides in plasma by LC-MS/MS: Application to clinical pharmacokinetics. Pharm. Biomed. Anal., 144: 25–30.
WHO TRS N 937 (2006) Additional guidance for organization performing in vivo bioequivalence studies. — Annex 9.