OBJECTIVE: To evaluate the bioequivalence of a gliclazide/metformin combination tablet (at dose of 80/500 mg) with co-administration of metformin (500 mg) and gliclazide (80 mg) as individual tablets in healthy male Korean volunteers. SUBJECTS, MATERIALS AND METHODS: The study was conducted as an open-label, randomized, 2-period crossover design in 32 healthy male Korean volunteers who received a combination tablet of gliclazide/metformin at a dose of 80/500 mg or co-administration of gliclazide and metformin as individual tablets in each study period. There was a 7-day washout period between doses. Serum concentrations of gliclazide and metformin up to 32 hours after administration were determined using a validated HPLC method with UV detection. The pharmacokinetic parameters such as AUC0-t (the area under the curve from zero to the time), AUC0- yen (the area under the curve from zero to infinity), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life), were analyzed by non-compartmental analysis. Analysis of variance (ANOVA) was carried out using logarithmically transformed AUC0-t, AUC0- yen and Cmax, and untransformed tmax. In addition, blood glucose concentration was also logarithmically transformed and analyzed. Tolerability and safety profiles were also investigated. RESULTS: There were no significant differences between the single combination tablet and the individual tablets in AUC0-t, AUC0- yen, Cmax and blood glucose concentration. The point estimates (90% confidence intervals) for AUC0-t, AUC0- yen and Cmax were 1.0293 (0.9476 - 1.1178), 1.0253 (0.9185 - 1.1443) and 1.0425 (0.9986 - 1.0883) for gliclazide, and 0.9887 (0.9137 - 1.0697), 0.9915 (0.9189 - 1.0697) and 0.9882 (0.9295 - 1.0505) for metformin, respectively, satisfying the bioequivalence criteria of 80 - 125% as proposed by the US FDA and the Korean legislation. Significant F test values were found between the subjects and subject nested sequence (SEQ) for AUC0-t and Cmax, indicating substantial inter-subject variation in the pharmacokinetics of gliclazide and metformin. However, a SEQ effect in the two-way crossover design did not impair the bioequivalence conclusion. No statistically significant differences were found for tmax and blood glucose concentration between two treatments. CONCLUSION: The combination tablet of gliclazide/metformin is bioequivalent to co-administration of individual tablets. As a result, the combination tablets are regarded therapeutically equivalent and exchangeable to the co-administration of individual tablets in clinical practice. Moreover, the combination tablets are expected to improve convenience and adherence to prescribed therapy and to contribute to better blood glucose control for patients with Type 2 diabetes.
RCT Entities:
OBJECTIVE: To evaluate the bioequivalence of a gliclazide/metformin combination tablet (at dose of 80/500 mg) with co-administration of metformin (500 mg) and gliclazide (80 mg) as individual tablets in healthy male Korean volunteers. SUBJECTS, MATERIALS AND METHODS: The study was conducted as an open-label, randomized, 2-period crossover design in 32 healthy male Korean volunteers who received a combination tablet of gliclazide/metformin at a dose of 80/500 mg or co-administration of gliclazide and metformin as individual tablets in each study period. There was a 7-day washout period between doses. Serum concentrations of gliclazide and metformin up to 32 hours after administration were determined using a validated HPLC method with UV detection. The pharmacokinetic parameters such as AUC0-t (the area under the curve from zero to the time), AUC0- yen (the area under the curve from zero to infinity), Cmax (maximum serum concentration), tmax (time to reach Cmax) and t1/2 (terminal half-life), were analyzed by non-compartmental analysis. Analysis of variance (ANOVA) was carried out using logarithmically transformed AUC0-t, AUC0- yen and Cmax, and untransformed tmax. In addition, blood glucose concentration was also logarithmically transformed and analyzed. Tolerability and safety profiles were also investigated. RESULTS: There were no significant differences between the single combination tablet and the individual tablets in AUC0-t, AUC0- yen, Cmax and blood glucose concentration. The point estimates (90% confidence intervals) for AUC0-t, AUC0- yen and Cmax were 1.0293 (0.9476 - 1.1178), 1.0253 (0.9185 - 1.1443) and 1.0425 (0.9986 - 1.0883) for gliclazide, and 0.9887 (0.9137 - 1.0697), 0.9915 (0.9189 - 1.0697) and 0.9882 (0.9295 - 1.0505) for metformin, respectively, satisfying the bioequivalence criteria of 80 - 125% as proposed by the US FDA and the Korean legislation. Significant F test values were found between the subjects and subject nested sequence (SEQ) for AUC0-t and Cmax, indicating substantial inter-subject variation in the pharmacokinetics of gliclazide and metformin. However, a SEQ effect in the two-way crossover design did not impair the bioequivalence conclusion. No statistically significant differences were found for tmax and blood glucose concentration between two treatments. CONCLUSION: The combination tablet of gliclazide/metformin is bioequivalent to co-administration of individual tablets. As a result, the combination tablets are regarded therapeutically equivalent and exchangeable to the co-administration of individual tablets in clinical practice. Moreover, the combination tablets are expected to improve convenience and adherence to prescribed therapy and to contribute to better blood glucose control for patients with Type 2 diabetes.