Effect of a Standardized Meal on the Bioavailability of Tibolone
Effect of a Standardized Meal on the Bioavailability of Tibolone
Study Objective. To assess the effect of food on absorption and pharmacokinetic disposition of tibolone.
Design. Open-label, randomized, crossover study with a 1-week washout period.
Setting. Institut für Klinische Pharmakologie, Höhenkirchen-Siegertsbrunn, Germany.
Subjects. Twenty-four healthy, early postmenopausal women.
Intervention. Single doses of tibolone 2.5 mg were administered after subjects consumed a high-fat meal or fasted.
Measurements and Main Results. Plasma concentrations of tibolone and its three primary metabolites, D-tibolone, 3a-hydroxytibolone, and 3é-hydroxytibolone, were assayed by gas chromatography with mass spectrometry. Peak plasma concentration (Cmax), time to Cmax, area under the plasma concentration versus time curve from time zero to infinity (AUC0-infinity), and elimination half-life were calculated, and food effects were evaluated. Plasma concentrations of tibolone and D-tibolone were too low to estimate AUC0-infinity and half-life. Absorption or formation of 3a-hydroxytibolone and 3é-hydroxytibolone was slower in fed participants than in fasting participants, but this was of no clinical relevance because of the long-term nature of tibolone treatment. Meal consumption did not affect AUC0-infinity or half-life for 3a-hydroxytibolone and 3é-hydroxytibolone.
Conclusion. Food consumption decreased and delayed Cmax but had no effect on the exposure of tibolone and its metabolites. Tibolone therefore can be administered irrespective of meal timing.
Tibolone [(7a,17a)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one; Org OD 14] is a tissue-specific compound that has favorable effects on bone, vaginal tissue, climacteric symptoms, mood, and sexual well-being in postmenopausal women, without causing estrogen-like stimulation of the endometrium and breast. Tibolone 2.5 mg is marketed as Livial in more than 70 countries for the treatment of climacteric symptoms and, in some countries, also for the prevention and treatment of osteoporosis.
After oral administration, tibolone is rapidly converted by the intestine and liver into two estrogenic metabolites, 3a-hydroxytibolone and 3é-hydroxytibolone, which are responsible for the drug's estrogenic effects on bone, vaginal tissue, and climacteric symptoms. A third metabolite, the D-isomer, has progestagenic and androgenic activities and is formed specifically in the endometrium. Therefore, the endometrium is not stimulated by tibolone. The chemical structures of tibolone and its major metabolites are shown in Figure 1.
(Enlarge Image)
Chemical structures of tibolone and its major metabolites.
Clinical studies have shown that the optimal dosage of tibolone for the treatment of climacteric symptoms is 2.5 mg/day, and in double-blind studies, 1.25 and 2.5 mg/day were both effective in preventing loss of bone mass.
Our study is one of a series that describes, for the first time, the pharmacokinetic characteristics of tibolone. The aim of the study was to assess the effect of a standardized meal on the bioavail-ability of a single oral dose of tibolone 2.5 mg based on plasma concentrations of tibolone and its primary metabolites in healthy, early post-menopausal women.
Study Objective. To assess the effect of food on absorption and pharmacokinetic disposition of tibolone.
Design. Open-label, randomized, crossover study with a 1-week washout period.
Setting. Institut für Klinische Pharmakologie, Höhenkirchen-Siegertsbrunn, Germany.
Subjects. Twenty-four healthy, early postmenopausal women.
Intervention. Single doses of tibolone 2.5 mg were administered after subjects consumed a high-fat meal or fasted.
Measurements and Main Results. Plasma concentrations of tibolone and its three primary metabolites, D-tibolone, 3a-hydroxytibolone, and 3é-hydroxytibolone, were assayed by gas chromatography with mass spectrometry. Peak plasma concentration (Cmax), time to Cmax, area under the plasma concentration versus time curve from time zero to infinity (AUC0-infinity), and elimination half-life were calculated, and food effects were evaluated. Plasma concentrations of tibolone and D-tibolone were too low to estimate AUC0-infinity and half-life. Absorption or formation of 3a-hydroxytibolone and 3é-hydroxytibolone was slower in fed participants than in fasting participants, but this was of no clinical relevance because of the long-term nature of tibolone treatment. Meal consumption did not affect AUC0-infinity or half-life for 3a-hydroxytibolone and 3é-hydroxytibolone.
Conclusion. Food consumption decreased and delayed Cmax but had no effect on the exposure of tibolone and its metabolites. Tibolone therefore can be administered irrespective of meal timing.
Tibolone [(7a,17a)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one; Org OD 14] is a tissue-specific compound that has favorable effects on bone, vaginal tissue, climacteric symptoms, mood, and sexual well-being in postmenopausal women, without causing estrogen-like stimulation of the endometrium and breast. Tibolone 2.5 mg is marketed as Livial in more than 70 countries for the treatment of climacteric symptoms and, in some countries, also for the prevention and treatment of osteoporosis.
After oral administration, tibolone is rapidly converted by the intestine and liver into two estrogenic metabolites, 3a-hydroxytibolone and 3é-hydroxytibolone, which are responsible for the drug's estrogenic effects on bone, vaginal tissue, and climacteric symptoms. A third metabolite, the D-isomer, has progestagenic and androgenic activities and is formed specifically in the endometrium. Therefore, the endometrium is not stimulated by tibolone. The chemical structures of tibolone and its major metabolites are shown in Figure 1.
(Enlarge Image)
Chemical structures of tibolone and its major metabolites.
Clinical studies have shown that the optimal dosage of tibolone for the treatment of climacteric symptoms is 2.5 mg/day, and in double-blind studies, 1.25 and 2.5 mg/day were both effective in preventing loss of bone mass.
Our study is one of a series that describes, for the first time, the pharmacokinetic characteristics of tibolone. The aim of the study was to assess the effect of a standardized meal on the bioavail-ability of a single oral dose of tibolone 2.5 mg based on plasma concentrations of tibolone and its primary metabolites in healthy, early post-menopausal women.
