Planning and Evaluation of Bioequivalence Studies of Enalapril Products

Nowadays retrospective analysis of bioequivalence studies of medicinal products that have the same International Nonproprietary Name is becoming particularly relevant. Over the past years we have accumulated a sufficient pool of data in the Russian Federation which make it possible to identify many differences, difficulties and errors associated with bioequivalence studies (especially those of highly variable drugs). Given that inhibitors of angiotensin-converting enzyme (ACE) can be highly variable, we conducted a retrospective analysis of bioequivalence studies of domestically-produced and foreign-made generic enalapril products. This article presents the results of the analysis whose aim was to determine intraindividual coefficients of variation and harmonise approaches to planning and evaluation of enalapril bioequivalence studies. It was demonstrated that enalapril products do not show high variability – both in terms of the original compound and the active metabolite. However, the analysis revealed many differences in the study designs: recruitment of a different number of healthy volunteers; determination of the concentration of either the original compound only, or in combination with the active metabolite; various analytical methods used for determination of analytes; different duration of blood sampling; and different sampling time points. The revealed differences made it possible to standardise the key research parameters, to harmonise them with the current requirements for conducting bioequivalence studies, and to formulate recommendations for planning and evaluation of enalapril studies. With respect to the study design, in addition to the standard conditions, the following can be recommended: at least 18 healthy volunteers should participate in enalapril bioequivalence studies; the pharmacokinetic parameters should be determined for both enalapril and its main active metabolite (enalaprilat); the duration of blood analyte determination should be at least 24 hours; the washout period should be 7 days; blood sampling for estimation of the maximum concentration should be more frequent around one hour after administration for enalapril and after three hours for enalaprilat.

bioequivalence study, highly variable drugs, inhibitors of angiotensin-converting enzyme, enalapril, enalaprilat

1. Ромодановский ДП, Драницына МА, Горячев ДВ, Ниязов РР, Гавришина ЕВ. Планирование дизайна и оценка результатов исследований биоэквивалентности высоковариабельных препаратов на примере розувастатина. Экспериментальная и клиническая фармакология. 2015;78(6):19–25. [Romodanovsky DP, Dranitsyna MA, Goryachev DV, Niyazov RR, Gavrishina EV. Design planning and evaluation of the results of bioequivalence studies of highly variable drugs using rosuvastatin as an example. Eksperimentalnaya i klinicheskaya farmakologiya=Experimental and Clinical Pharmacology. 2015;78(6):19–25 (In Russ.)] https://doi.org/10.30906/0869-2092-2015-78-6-19-25

2. Ромодановский ДП, Еременкова ТВ, Драницына МА, Горячев ДВ, Ниязов РР, Гавришина ЕВ, Меркулов ВА. Высоковариабельные лекарственные препараты – особенности исследования биоэквивалентности. Ведомости Научного центра экспертизы средств медицинского применения. 2015;(4):5–10. [Romodanovsky DP, Eremenkova TV, Dranitsyna MA, Goryachev DV, Niyazov RR, Gavrishina EV, Merkulov VA. Highly variable medicines – specific aspects of bioequivalence studies. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya=Тhе Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2015;(4):5–10 (In Russ.)]

3. Davit BM, Conner DP, Fabian-Fritsch B, Haidar SH, Jiang X, Patel DT, et al. Highly variable drugs: observations from bioequivalence data submitted to the FDA for new generic drug applications. AAPS J. 2008;10(1):148–56. https://doi.org/10.1208/s12248-008-9015-x

4. Davit BM, Chen ML, Conner DP, Haidar SH, Kim S, Lee CH, et al. Implementation of a reference-scaled average bioequivalence approach for highly variable generic drug products by the US Food and Drug Administration. AAPS J. 2012;14(4):915–24. https://doi.org/10.1208/s12248-012-9406-x

5. Tothfalusi L, Endrenyi L, Arieta AG. Evaluation of bioequivalence for highly variable drugs with scaled average bioequivalence. Clin Pharmacokinet. 2009;48:725–43. https://doi.org/10.2165/11318040-000000000-00000.

6. Жердев ВП, Колыванов ГБ, Литвин АА, Сариев АК. Гармонизация проведения исследований биоэквивалентности лекарственных препаратов: вопросы и их возможное решение. Экспериментальная и клиническая фармакология. 2003;66(2):60–4. [Zherdev VP, Kolyvanov GB, Litvin AA, Sariev AK. Harmonization of testing drugs for bioequivalence: problems and solutions. Eksperimentalnaya i klinicheskaya farmakologiya=Experimental and Clinical Pharmacology. 2003;66(2):60–4 (In Russ.)] https://doi.org/10.30906/0869-2092-2003-66-2-60-64

7. Смирнов АС, Шнайдер А, Фролов МЮ, Петров ВИ. Современные критерии исследований биоэквивалентности лекарственных средств: гармонизация национальных стандартов. Химико-фармацевтический журнал. 2014;48(5):3–10. [Smirnov AS, Schneider А, Frolov МYu, Petrov VI. Modern criteria of bioequivalence of pharmaceuticals: harmonization of national standards. Khimiko-farmatsevticheskiy zhurnal=Pharmaceutical Chemistry Journal. 2014;48(5):3–10 (In Russ.)]

8. Ромодановский ДП, Горячев ДВ. Актуальные аспекты планирования дизайна исследований биоэквивалентности препаратов аторвастатина. Ведомости Научного центра экспертизы средств медицинского применения. 2013;(1):22–7. [Romodanovsky DP, Goryachev DV. Current aspects of planning bioequivalence studies design for atorvastatin preparations. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya=Тhе Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2013;(1):22–7 (In Russ.)]