Pharmacokinetic and Pharmacodynamic Profiles of a Fixed-Dose Combination of Olmesartan Medoxomil and Amlodipine in Healthy Chinese Males and Females

Abstract

This study investigated the pharmacokinetics and pharmacodynamics of a fixed-dose combination (FDC) tablet of olmesartan medoxomil 20mg and amlodipine 5mg (CS-8663) in healthy Chinese subjects. This single-centre, open-label study was conducted in five healthy males and five females aged 18-45years. Subjects received a single oral dose of an olmesartan medoxomil/amlodipine 20mg/5mg 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. After oral administration, the peak concentrations of olmesartan and amlodipine were reached in a median time of 2 and 6h, 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 8days. Similar significant reductions of systolic and diastolic blood pressure were observed after a single dose of an olmesartan medoxomil/amlodipine 20mg/5mg FDC tablet. In comparison, multiple doses of olmesartan medoxomil/amlodipine 20mg/5mg 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 20mg/5mg FDC tablets was safe and well tolerated. After single and multiple doses of olmesartan medoxomil/amlodipine 20mg/5mg 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 20mg/5mg FDC tablet after a single dose and stabilization of such effects after multiple doses.