Bioequivalence Study of Generic Tablet Formulations Containing Ethinylestradiol and Chlormadinone Acetate in Healthy Female Volunteers

Abstract

The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol (CAS 57-63-6) and Chlormadinone acetate (CAS 302-22-7) (Bellissima® 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_max) of ethinylestradiol were 124.96 pg/ml (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–∞) of ethinylestradiol were 1292.35 pg/mlh (test) and 1380.49 pg/ml · h (reference). For Chlormadinone acetate, geometric means of AUC_0–∞ 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–∞ and C_max were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90 % confidence intervals for the AUC_0–∞ 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–∞ 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–∞ and C_max fall into the generally accepted range of 80%–125%.

Key words

Bellissima® - Bioequivalence - CAS 57-63-6 - CAS 302-22-7 - Chlormadinone acetate - Ethinylestradiol

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