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.

Pharmacokinetic study in women of three different doses of a new formulation of oral testosterone undecanoate, Andriol Testocaps.

STUDY OBJECTIVE: To assess the pharmacokinetic parameters of testosterone undecanoate after administration of a new oral formulation, Andriol Testocaps. DESIGN: Randomized, open-label, group-comparative, parallel-design, dose-proportionality study. SETTING: Clinical pharmacology unit. SUBJECTS: Forty-five healthy women without childbearing potential. INTERVENTION: Two oral doses each of testosterone undecanoate 20, 40, or 80 mg were administered with meals, separated by a 12-hour dosing interval. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of testosterone undecanoate were assayed by liquid chromatography with mass spectrometric detection, and of testosterone and 5alpha-dihydrotestosterone (DHT) by gas chromatography with mass spectrometric detection. Pharmacokinetic parameters were calculated using standard methods. Statistical analysis of dose proportionality was performed on the log(e)-transforms of dose-normalized area under the serum concentration-time curve from 0-12 hours (AUC(0-12)) and from zero to the sampling time of the last measurable concentration after administration of the second dose (AUC(0-t(last)), and maximum serum concentration after the first dose (C(max)l). For testosterone undecanoate, testosterone, and DHT, dose-related increases in plasma concentrations were found with increasing doses of testosterone undecanoate; maximum concentrations were found 5-7 hours after administration. Using baseline-corrected testosterone values, dose proportionality for testosterone was found for AUC(0-12), AUC(0-t)(last), and C(max)(l). After higher doses, plasma levels of testosterone undecanoate were higher and plasma levels of DHT lower than could be expected assuming dose proportionality. CONCLUSION: Serum testosterone levels are dose proportional after oral administration of two doses of a new formulation of testosterone undecanoate 20, 40, and 80 mg, Andriol Testocaps.

Important effect of food on the bioavailability of oral testosterone undecanoate.

STUDY OBJECTIVE: To assess the effects of food on the bioavailability of testosterone undecanoate, testosterone, and 5alpha-dihydrotestosterone (DHT) after administration of a new oral testosterone undecanoate formulation, Andriol Testocaps. DESIGN: Randomized, open-label, crossover study with a 1-week washout period. SETTING: Clinical pharmacology unit. SUBJECTS: Sixteen healthy postmenopausal women. INTERVENTION: Single oral doses of testosterone undecanoate 80 mg were administered either during a fasting period or after consumption of a standardized continental breakfast. MEASUREMENTS AND MAIN RESULTS: Serum concentrations of testosterone undecanoate were assayed by liquid chromatography with mass spectrometry detection; testosterone and DHT were assayed by gas chromatography with mass spectrometry detection. Serum concentrations of testosterone, testosterone undecanoate, and DHT were low to negligible when testosterone undecanoate was administered to subjects in a fasting state; these values were significantly higher when the test drug was coadministered with food. For testosterone, the maximum serum concentration and area under the plasma concentration-time curve were 0.67 ng/ml and 5.37 ng x hr/ml, respectively, in the fasting state, versus 10.7 ng/ml and 56.4 ng x hr/ml, respectively, in the fed state. The same parameters were also significantly higher for testosterone undecanoate and DHT in the fed versus fasting subjects. CONCLUSION: Food increases the bioavailability of testosterone undecanoate, testosterone, and DHT. For proper absorption, Andriol Testocaps must be taken with meals.