Dose proportionality of three different doses of tibolone.

STUDY OBJECTIVE: To assess dose proportionality of tibolone tablets after multiple oral administration. DESIGN: Open-label, randomized, three-period crossover study SETTING: Department of Drug Metabolism and Kinetics, N.V. Organon, Oss, The Netherlands. SUBJECTS: Twenty-seven postmenopausal women aged 65 years or younger. INTERVENTION: Subjects received tibolone 1.25, 2.5, or 5.0 mg once/day for 7 days. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of tibolone and its three primary metabolites were assayed. Steady state was attained by day 5. Elimination half-life for 3alpha-hydroxytibolone was 7.2-8.5 hours. At steady state, the dose-normalized peak concentration and area under the curve satisfied bioequivalence requirements for the 1.25- and 2.5-mg doses, but not fully for the 5.0-mg dose. Parameters were proportionally slightly lower for the 5.0-mg dose compared with the 1.25- and 2.5-mg doses. CONCLUSION: Proportional bioequivalence was established for the 1.25- and 2.5-mg doses, but not between the 5.0-mg dose and the two lower doses of tibolone.