Pharmacokinetic and pharmacodynamic profiles of a fixed-dose combination of olmesartan medoxomil and amlodipine in healthy Chinese males and females

Abstract

Objectives: This study investigated the pharmacokinetics and pharmacodynamics of a fixed-dose combination (FDC) tablet of olmesartan medoxomil 20 mg and amlodipine 5 mg (CS-8663) in healthy Chinese subjects.

Methods: This single-centre, open-label study was conducted in five healthy males and five females aged 18-45 years. Subjects received a single oral dose of an olmesartan medoxomil/amlodipine 20 mg/5 mg tablet on Day 1 under fasting conditions, and after a wash-out period they received the same dose once daily from Day 15 to Day 24. Serial blood samples were collected at predefined time-points to measure the plasma concentrations of olmesartan and amlodipine during the single-dose and the multiple-dose period. Meanwhile, blood pressure and heart rate were repeatedly taken to delineate the pharmacodynamic profiles. Safety was assessed throughout the study.

Results: After oral administration, the peak concentrations of olmesartan and amlodipine were reached in a median time of 2 and 6 h, respectively. The elimination half-life of amlodipine is more than twice as long as that of olmesartan. Steady states of both compounds were attained after once-daily dosing for 8 days. Similar significant reductions of systolic and diastolic blood pressure were observed after a single dose of an olmesartan medoxomil/amlodipine 20 mg/5 mg FDC tablet. In comparison, multiple doses of olmesartan medoxomil/amlodipine 20 mg/5 mg tablets lowered the daily pre-dose BP level and led to smaller BP changes after the last dose. Heart rate increments were larger and more sustained after multiple doses than during the single-dose period. Females showed more systolic BP reductions than males despite inter-sex similarity in pharmacokinetics. Treatment with olmesartan medoxomil/amlodipine 20 mg/5 mg FDC tablets was safe and well tolerated.

Conclusion: After single and multiple doses of olmesartan medoxomil/amlodipine 20 mg/5 mg FDC tablets the pharmacokinetic profiles of olmesartan or amlodipine were comparable to those reported for monotherapy with olmesartan medoxomil or amlodipine, except that the elimination half-life of olmesartan was longer because of the longer time course over which pharmacokinetic blood sampling was carried out in this study. The response profiles of BP indicate a concentration-dependent antihypertensive effect of the olmesartan medoxomil/amlodipine 20 mg/5 mg FDC tablet after a single dose and stabilization of such effects after multiple doses.