Effects of food on the bioavailability of gepirone from extended-release tablets in humans: results of two open-label crossover studies.

BACKGROUND: The new antidepressant gepirone acts preferentially on 5-hydroxytryptamine type 1A (5-HT1A) receptors and functions as a 5-HT1A agonist. Placebo-controlled clinical studies have established that gepirone has a good safety profile and is effective for the treatment of depression. A previous study showed that administration of gepirone immediate release 15 minutes after a meal instead of during a fast increased the mean area under the plasma concentration-time curve (AUC) by 37%. Gepirone was reformulated into extended release (ER), which necessitated further exploration of the effects of food on bioavailability. OBJECTIVE: This article describes 2 studies of the pharmacokinetic properties of gepirone ER and 1 of its metabolites, 1(2-pyrimidinyl)-piperazine (1-PP), in healthy subjects. In study 1, we assessed the effects of food and the influence of time of food intake relative to dosing on the bioavailability of gepirone ER. The objective of study 2 was to confirm that gepirone ER has similar pharmacokinetic characteristics under fed and fasting conditions. METHODS: Two open-label, randomized, single-dose, crossover studies balanced for first-order residual effects were conducted to assess the bioavailability of gepirone from ER tablets. Healthy male subjects received a 20-mg oral dose of gepirone ER. In study 1, subjects took the gepirone ER dose after a 10-hour overnight fast or 1 hour before, 15 minutes after, or 2 hours after a standard high-fat meal. In study 2, subjects either took the gepirone ER dose after a 10-hour overnight fast and continued to fast for 4 more hours or took the gepirone ER dose 15 minutes after a standard high-fat meal. RESULTS: Twenty-eight men (mean [SD] age, 27.2 [6.6] years) participated in study 1, and 27 men (mean [SD] age, 31.8 [9.6] years) participated in study 2. In study 1, the mean (SD) maximum peak plasma concentration (Cmax) for gepirone ER was 69.2% higher (3.25 [1.71] vs 1.92 [0.96] ng/mL) (P≤0.05) and the AUC from time 0 to 30 hours for gepirone ER was 31.9% higher (39.3 [20.6] vs 29.8 [15.3] ng/mL·h) (P≤0.05) for the 15-minute postprandial dose than for the fasting dose, respectively. In study 2, the mean Cmax for gepirone was 62.0% higher (4.13 vs 2.55 ng/mL) and the mean AUC from time 0 to infinity for gepirone was 24% higher (38.71 vs 31.14 ng/mL·h) for the postprandial dose than for the fasting dose (P<0.05). All reported adverse effects were mild to moderate in intensity, and most (study 1) or all (study 2) occurred during the fasting state. CONCLUSIONS: When administered with food, the bioavailability (AUC and Cmax) of gepirone ER was greater than during the fasting state, with the greatest bioavailability seen when the drug was taken 15 minutes after eating. Based on this pharmacokinetic analysis, it may be prudent to administer gepirone ER consistently, either always with or always without food.

Effect of a standardized meal on the bioavailability of a single oral dose of tibolone 2.5 mg in healthy postmenopausal 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, Hohenkirchen-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, delta4-tibolone, 3alpha-hydroxytibolone, and 3beta-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 (AUC(0-infinity)), and elimination half-life were calculated, and food effects were evaluated. Plasma concentrations of tibolone and delta4-tibolone were too low to estimate AUC(0-infinity) and half-life. Absorption or formation of 3alpha-hydroxytibolone and 3beta-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 AUC(0-infinity) or half-life for 3alpha-hydroxytibolone and 3beta-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.

Effect of renal impairment on the pharmacokinetics of a single oral dose of tibolone 2.5 mg in early postmenopausal women.

STUDY OBJECTIVE: To determine the influence of renal function on the pharmacokinetics of tibolone and its primary metabolites, delta4-tibolone, 3alpha-hydroxytibolone, and 3beta-hydroxytibolone. DESIGN: Open-label, single-center, single-dose study SETTING: Drug research center, Balatonfüred, Hungary. SUBJECTS: Twenty-four postmenopausal women aged 45-65 years. INTERVENTION: Subjects were assigned to one of four groups based on their renal function, as assessed by glomerular filtration rate (normal to severely impaired), and received a single dose of tibolone 2.5 mg. Pharmacokinetic parameters of tibolone and its primary metabolites were derived from blood samples taken at predefined intervals for up to 48 hours after tibolone administration. Pharmacokinetic parameters were calculated using standard noncompartmental methods and compared by analysis of covariance. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic parameters of tibolone and its primary metabolites were similar in subjects with normal to severely impaired renal function. Pharmacokinetic profiles of tibolone and its metabolites were independent of the degree of renal impairment. CONCLUSION: Pharmacokinetic parameters of tibolone were not affected by varying degrees of renal function.

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.