The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol (CAS 57-63-6) and chlormadinone acetate (CAS 302-22-7) (Bellissima (R) as test and the respective preparation from the originator as reference) were investigated in 20 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomised, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken up to 168 h post-dose, and ethinylestradiol and chlormadinone acetate plasma concentrations were determined with a validated LC-MS/MS method. The observed mean maximum plasma concentrations (C.) of ethinylestradiol were 124.96 pg/mlh (test) and 129.12 pg/ml (reference). In the case of chlormadinone acetate, C(max) averaged 6.9566 ng/ml (test) and 6.6663 ng/m (reference). The geometric means of area under the plasma concentration-time curve (AUC(0-infinity)) of ethinylestradiol were 1292.35 pg/mlh (test) and 1380.49 pg/ml . h (reference). For chlormadinone acetate, geometric means of AUC(0-infinity) were 53.322 ng/ml . h (test) and 58.111 ng/ml . h (reference). The median of t(max) of ethinylestradiol was 1.5 h for both test and reference and the median of t(max) of chlormadinone acetate 1.0 h (test) and 1.5 h (reference). Plasma elimination half-lives (t(1/2)) of ethinylestradiol were 14.96 h (test) and 15.41 h (reference) and of chlormadinone acetate 56.63 h (test) and 56.17 h (reference), respectively. Both primary target parameters AUC(0-infinity) and C(max) were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90% confidence intervals for the AUC(0-infinity) ratio (test/reference: 93.72% [86.62%-101.39%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for C(max) of ethinylestradiol, as the point estimator and the 90% confidence interval for the C(max) ratio are 96.18% (90.82%-101.86%). Regarding the AUC(0-infinity) ratio of chlormadinone acetate, the point estimator is 91.60% and the 90% confidence interval 84.08%-99.79%. Furthermore, exchangeability of both formulations is also suggested by the point estimator and 90% confidence of C(max) of this active agent (104.72% [95.76%-114.53%]). Bioequivalence between test and reference formulation was demonstrated since for both ethinylestradiol and chlormadinone acetate all 90% confidence intervals of AUC(0-infinity) and C(max) fall into the generally accepted range of 80%-125%.
