薬理と治療

Abstract

Background and Objectives For the development of fixed-dose combination tablet, the bioequivalence and the food-effect on bioavailability between the fixed-dose combination and each tablet are needed. The study objectives were to investigate the bioequivalence of fixed-dose triple combination of telmisartan 80 mg, amlodipine 5 mg and hydrochlorothiazide 12.5 mg(T80/A5/H12.5 mg), compared to co-administration of telmisartan 80 mg/amlodipine 5 mg combination tablet plus hydrochlorothiazide 12.5 mg tablet(T80/A5 mg+H12.5 mg)or to co-administration of telmisartan 80 mg/hydrochlorothiazide 12.5 mg combination tablet plus amlodipine 5 mg tablet (T80/H12.5 mg+A5 mg). In addition, the food-effect of this triple combination on the pharmacokinetics were investigated. Methods Bioequivalences were assessed in 72 Japanese healthy male adult volunteers by an open-label, randomized, single-dose, 2-group, 4-period replicated crossover design, with a washout period of at least 14 days. The food effect was assessed in 36 volunteers by an open-label, single-dose, 1 add-on period(2-period fixed-sequence for 1 group)design with a washout period of at least 14 days[NCT02121535, NCT02129192]. Results The comparison between T80/A5/H12.5 mg and either the co-administration of T80/A5 mg+H12.5 mg, or the co-administration of T80/H12.5 mg+A5 mg, revealed that, for the Cmax and AUC0-tz of telmisartan, amlodipine and hydrochlorothiazide, the two-sided 90% confidence intervals for the geometric mean ratios of T80/A5/H12.5 mg to the respective co-administration therapies were within the bioequivalence criteria(80% to 125%). In addition, the two-sided 90% confidence intervals for the geometric mean ratios suggested that the Cmax and AUC0-tz of telmisartan and the Cmax of hydrochlorothiazide were reduced by food intake. However, foods did not affect the pharmacokinetics of amlodipine. The safety profile of all of T80/A5/H12.5 mg, co-administration of T80/A5 mg+H12.5 mg, and co-administration of T80/H12.5 mg+A5 mg were similar and in line with what was already known regarding the safety profile of each of the drugs in the combination. Conclusions Bioequivalence was proven between T80/A5/H12.5 mg and either co-administration of T80/A5 mg+H12.5 mg, or T80/H12.5 mg+A5 mg. The food effect on each ingredient of T80/A5/H12.5 mg was similar to that observed with T80/A5 mg and T80/H12.5 mg.