Comparison of the pharmacokinetics of fosfluconazole and fluconazole after single intravenous administration of fosfluconazole in healthy Japanese and Caucasian volunteers.

OBJECTIVES: To investigate the bioavailability of fluconazole (FLCZ) from fosfluconazole (phosphate pro-drug of FLCZ) and to compare the pharmacokinetics of fosfluconazole and FLCZ in Japanese and Caucasian subjects. METHODS: In a randomised, double-blind, double-dummy, single-dose, two-period, crossover study, 12 Japanese and 12 Caucasian healthy subjects received a bolus intravenous injection of 1000 mg fosfluconazole or an intravenous infusion of 800 mg FLCZ in random order. Concentrations of fosfluconazole and FLCZ were determined in plasma and urine samples taken up to 144 h and 48 h post-dose, respectively. RESULTS: The bioavailability of FLCZ after administration of fosfluconazole was 95.2% (95% confidence interval: 89.0, 102.0) in Japanese subjects and 100.6% (94.0, 107.7) in Caucasian subjects. The ratio of bioavailabilities (Japanese/Caucasian) was 94.7% (86.0, 104.3). There were no statistically significant differences in the pharmacokinetic parameters of fosfluconazole (except for AUC(inf)) and FLCZ between Japanese and Caucasian subjects. Although mean AUC(inf) of fosfluconazole was 25.6% (5.6, 49.2) greater in Japanese subjects, the lack of a statistically significant difference in weight-adjusted CL of fosfluconazole demonstrates that the difference in AUC(inf) was due to a difference in body weight. The adverse-event profile was similar in Japanese and Caucasian subjects after both fosfluconazole and FLCZ dosing, and both treatments were well tolerated in each group. CONCLUSIONS: The pharmacokinetics of fosfluconazole and FLCZ were similar in Japanese and Caucasian subjects. Fosfluconazole is almost completely converted to FLCZ and similar systemic exposure to FLCZ is achieved after single doses of fosfluconazole in both Japanese and Caucasian subjects.

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.

Galantamine pharmacokinetics, safety, and tolerability profiles are similar in healthy Caucasian and Japanese subjects.

The aim of this study was to compare the pharmacokinetics of galantamine in healthy Japanese and Caucasian subjects and assess the safety and tolerability of galantamine in both ethnic groups. Parallel groups of healthy Japanese (n = 13; 6 males and 7 females)and Caucasian (n = 12; 6 males and 6 females) subjects matched for weight and age received single oral doses of galantamine 4 mg, or galantamine 8 mg, or placebo in a double-blind, three-way crossover trial according to a randomized dosing schedule. Concentrations of galantamine and norgalantamine were determined in plasma and urine samples taken up to 48 and 24 hours after dosing, respectively. Safety and tolerability were monitored throughout the trial by recording adverse events, laboratory tests, and cardiovascular parameters. The mean plasma concentration-time profiles of galantamine were very similar after single doses of galantamine (4 and 8 mg), and there was an approximate dose proportionality of galantamine pharmacokinetic parameters in both Caucasian and Japanese ethnic groups. The mean (+/- SD) pharmacokinetic parameters in the two ethnic groups did not show any clinically relevant differences. The ratios for the area under the plasma-concentration curve from time zero to infinity (AUC)0-infinity) in Japanese:Caucasian subjects with 4 and 8 mg doses were 103% (90% confidence interval [CII = 92-116) and 107% (90% CI = 94-121), respectively. Ratios for maximum plasma concentration (Cmax) values were 107% (90% CI= 90-127) and 108% (90% CI= 95-123), respectively. These ratios and associated 90% CIs were within the 80% to 125% range limit of bioequivalence. Analysis of variance (ANOVA) showed that these ratio values demonstrated no statistically significant difference between the two ethnic groups. There was no overt difference in the adverse event profile in Japanese subjects compared with Caucasian subjects. There were no serious adverse events, and no subjects discontinued from the study because of adverse events. No consistent or clinically relevant pattern of blood chemistry, hematology, or cardiovascular changes was seen. These results suggest that the pharmacokinetic profiles of galantamine after single-dose administration are not statistically significantly different between Caucasian and Japanese groups. Galantamine was well tolerated. The safety and tolerability of galantamine were very similar in the two ethnic groups.