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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.

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Acknowledgments

X. Chen, Q. Zhao, J. Jiang and P. Hu contributed to the conception and design of the research; X. Chen, P. Hu, T. Liu and W. Zhong were involved in the acquisition of data or analysis and interpretation of data; X. Chen and Q. Zhao were involved in the initial drafting of the manuscript and all authors critically reviewed and contributed to subsequent drafts. X. Chen, J. Jiang and P. Hu assisted in protocol development. X. Chen and H.Z. Liu were responsible for the evaluation and care of study subjects. The authors deeply appreciated the contributions of the study team during the conduct of this study, which included but were not limited to study nurses Wenying Liang, Shuhui Guo, Zhiyuan Zhang, Xiaowei Li, Chuanqing Yang, Li Sun, Qiqiong Ding, JunWang, Jing Yang; study coordinators Xin Jin, Shuxia Guan; study quality assurance and quality control Haiyan Cheng, Mingli Hu, Ran Li; and study data manager Jinghai Zhou. This study was sponsored by Daiichi Sankyo Pharmaceutical (Shanghai) Co., Ltd with an assigned protocol code of SS8663-03. The work was supported by a grant from the National Program on Key Research Project of New Drug Innovation (No. 2008ZX09312-016).The authors have no conflicts of interest that are directly relevant to the content of this article.

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Correspondence to Qian Zhao.

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Chen, X., Hu, P., Jiang, J. et al. Pharmacokinetic and Pharmacodynamic Profiles of a Fixed-Dose Combination of Olmesartan Medoxomil and Amlodipine in Healthy Chinese Males and Females. Clin Drug Investig 32, 783–790 (2012). https://doi.org/10.1007/s40261-012-0026-0

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Keywords

  • Amlodipine
  • Olmesartan
  • Olmesartan Medoxomil
  • Peking Union Medical College Hospital
  • Healthy Chinese Subject