Abstract
Angiotensin II receptor antagonists (ARAs) are one of the most promising classes of antihypertensive drugs. They are most widely represented on the Russian market by losartan drugs which total 24 items. Therefore, it is crucial to analyse the factors that may affect the results of comparison of generic and reference losartan drugs.The aim of the study was to perform a retrospective analysis of bioequivalence studies of generic losartan drugs in order to develop approaches to expert evaluation of research protocols and reports.Materials and methods: the retrospective analysis covered the results of 27 bioequivalence studies of losartan and included the calculation of the pharmacokinetic parameters Cmax and AUC0-t, their intra-individual variability, and the weighted average of intra-individual variability. The calculations were made for the pooled population of men and women, as well as separately for each gender.Results: the data obtained indicate borderline high variability of losartan in bioequivalence studies (for Cmax in 50 % of the studies). It was demonstrated that losartan drugs may have different pharmacokinetics in men and women in terms of Cmax and AUC0-t. The retrospective analysis of the data made it possible to formulate relevant expert approaches to evaluation of protocols and reports of bioequivalence studies of losartan drugs.Conclusions: Bioequivalence of losartan should be evaluated in three- or four-period, double crossover, two-sequence replicate design studies. The study has to determine the pharmacokinetic parameters of the starting compound and its active metabolite; the period of determination of analytes should be at least 36 hours; the washout period of 7 days is sufficient; blood sampling should be more frequent during the first hour after administration for losartan and during the first 3–4 hours for the metabolite. When determining the sample size, the weighted average of the coefficient of intra-individual variability of Cmax of losartan (33 %) should be taken into account. The bioequivalence margins for Cmax can be scaled up.
Highlights
Заболевания сердечно-сосудистой системы являются одной из важнейших медико-социальных проблем в Российской Федерации
MSE is the mean squared error; AUC0-t is the area under the concentration–time curve in the time interval from t = 0 to t = the time when the last blood sample was taken; Cmax is the maximum concentration of the drug in the blood; values showing high variability
MSE is the mean squared error; AUC0-t is the area under the concentration–time curve in the time interval from t = 0 to t = the time when the last blood sample was taken; Cmax is the maximum concentration of the active metabolite in the blood; values showing high variability are highlighted in bold. * The table provides data only for those studies which determined the active metabolite of losartan
Summary
Федеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения». Из них на рынке Российской Федерации наиболее широко представлены препараты лозартана —. Цель работы: проведение ретроспективного анализа исследований биоэквивалентности воспроизведенных препаратов лозартана для разработки подходов к экспертной оценке протоколов и отчетов исследований. Материалы и методы: в рамках ретроспективного анализа результатов 27 исследований биоэквивалентности лозартана проведен расчет фармакокинетических параметров C , AUC , значений их max. Результаты: полученные данные свидетельствуют о пограничной высокой вариабельности лозартана в исследованиях биоэквивалентности (для параметра Cmax в 50% исследований). Что препараты лозартана у мужчин и женщин могут иметь различия в фармакокинетике Cmax и AUC0-t. Ретроспективный анализ данных позволил сформулировать актуальные экспертные подходы к оценке протоколов и отчетов исследований биоэквивалентности препаратов лозартана. Выводы: оценивать биоэквивалентность лозартана следует в исследованиях с повторным дизайном в трех или четырех периодах, с двумя перекрестами, с двумя последовательностями приема препаратов. Границы признания биоэквивалентности могут быть масштабированы для Cmax. Ключевые слова: биоэквивалентность; исследования биоэквивалентности; лозартан; высокая вариабельность; половые различия
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