Bioequivalence study of two tablet formulations of ramipril in healthy volunteers

This study was conducted in order to assess the bioequivalence of a test and reference tablet formulation containing 10 mg of ramipril ((1S,5S,7S)-8-[(2S)-2-[[(1S)-1-ethoxycarbonyl-3-phenyl-propyl]amino]propanoyl] -8-azabicyclo[3.3.0]octane-7-carboxylic acid, CAS 87333-19-5). Forty healthy male and female volunteers were treated in a single-centre randomised, single-dose, open-label, 2-way crossover study, with a washout period of 35 days between treatments. Plasma samples were collected up to 168 h post-dosing for the determination of ramipril and its active metabolite, ramiprilat, by LC-MS/MS. The evaluation of bioequivalence was based on the following pharmacokinetic parameters that were calculated by standard non-compartmental methods: the area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration (AUCt) and that extrapolated to infinity (AUC) and the maximum observed concentration (C max). The 90% confidence interval of the ratios (test/reference) (obtained by analysis of variance, ANOVA) were 0.83-1.20 for Cmax of ramipril, 0.90-1.10 for Cmax of ramiprilat, 0.95-1.23 for AUC 0-48 of ramipril, 0.97-1.11 for AUC0-168 of ramiprilat, 0.96-1.23 for AUC of ramipril and 0.98-1.15 for AUC of ramiprilat, i. e. within the predefined acceptable range for the conclusion of bioequivalence. T max of the test formulation was 0.67 ± 0.33 h for ramipril and 2.28 ± 0.74 h for ramiprilat; Tmax of the reference formulation was 0.71 ± 0.32 h for ramipril and 2.40 ± 0.88 for ramiprilat. The ramipril and ramiprilat Tmax values estimated for the test and the reference formulations were not significantly different (p-value > 0.05). The study indicated that the test and reference formulations containing 10 mg of ramipril were equivalent in terms of both the rate and extent of bioavailability.