薬理と治療

Abstract

Background and Objectives It was known that there were no drug-drug interactions between telmisartan and either amlodipine or hydrochlorothiazide in the 2-agent combinations. However there are no investigation in 3-agent co-administration of telmisartan, amlodipine and hydrochlorothiazide. This study objective was to evaluate the relative bioavailability at steady-state between new antihypertensive fixed-dose triple combination of telmisartan, amlodipine and hydrochlorothiazide, and the fixed-dose combination drugs with two agents. Methods This trial was performed in 36 Japanese healthy male adult volunteers by an open-label, randomized, multiple-dose, 6-sequence, 3-period, 3-treatment crossover design using fixed-dose combinations of telmisartan 80 mg, amlodipine 5 mg and hydrochlorothiazide 12.5 mg(T80/A5/H12.5 mg), telmisartan 80 mg and hydrochlorothiazide 12.5 mg(T80/H12.5mg), or telmisartan 80 mg and amlodipine 5 mg(T80/A5 mg)[NCT02183675]. Each treatment was administered once daily for 10 days in fasted state in the morning. Results In all formulations, telmisartan reached Cmax,ss at 0.50-0.75 hours, and was eliminated with t1/2,ss of 23.6-27.1 hours. For AUCτ,ss, the 90% confidence intervals(CIs)for the geometric mean ratio of T80/A5/H12.5 mg to T80/H12.5 mg and to T80/A5 mg were within the bioequivalence criteria(80% to 125%). The 90% CIs for the geometric mean ratios of Cmax,ss slightly exceeded the upper limit of the criteria but the point estimate were 108.4%(vs. T80/H12.5 mg)and 114.9%(vs. T80/A5 mg), and 90% CIs included the unity. Amlodipine reached Cmax,ss at 8.00 hours, and was eliminated with t1/2,ss of 42.5-43.0 hours. The 90% CIs for the geometric mean ratios of Cmax,ss and AUCτ,ss were within the bioequivalence criteria. Hydrochlorothiazide reached Cmax,ss at 1.50 hours, and was eliminated with t1/2,ss of 10.3-11.1 hours. The 90% CIs for the geometric mean ratios of Cmax,ss, AUCτ,ss and urinary excretion (Ae0-24,ss)were within the bioequivalence criteria. The safety of T80/A5/H12.5 mg was similar to T80/H12.5 mg and T80/A5 mg. Conclusions Following multiple--dose administration of T80/A5/H12.5 mg, no clinically significant pharmacokinetic interactions were observed among the ingredients. The safety and tolerability of T80/A5/H12.5 mg were favorable, as with T80/H12.5 mg and T80/A5 mg.