Expert Approaches to the Assessment of Losartan Drugs Bioequivalence

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 C_max and AUC_0-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 C_max in 50 % of the studies). It was demonstrated that losartan drugs may have different pharmacokinetics in men and women in terms of C_max and AUC_0-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 C_max of losartan (33 %) should be taken into account. The bioequivalence margins for C_max can be scaled up.

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