Single-Center Evaluation of the Single-Dose Pharmacokinetics of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Renal Impairment
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Background and objective
Azilsartan medoxomil (AZL-M) is a potent angiotensin II receptor blocker that decreases blood pressure in a dose-dependent manner. It is a pro-drug and not detected in blood after oral administration because of rapid hydrolysis to the active moiety, azilsartan (AZL). AZL undergoes further metabolism to the major metabolite M-II and minor metabolites. The objective of this study was to determine the effect of renal impairment on the pharmacokinetics of AZL and its major metabolite.
This was a single-center, open-label, phase I parallel-group study which examined the single-dose (40-mg) pharmacokinetics of AZL and M-II in 24 subjects with mild, moderate, or severe renal impairment or end-stage renal disease requiring hemodialysis (n = 6 per group), respectively, and healthy matched subjects (n = 24).
Renal impairment/disease did not cause clinically meaningful increases in exposure to AZL. M-II exposure was higher in all renally impaired subjects and highest in those with severe impairment (approx fivefold higher vs. control). M-II is pharmacologically inactive; increased exposure was not considered important in dose selection for AZL-M in subjects with renal impairment. Hemodialysis did not significantly remove AZL or M-II. Renal impairment had no clinically meaningful effect on the plasma protein binding of AZL or M-II. Single doses of AZL-M 40 mg were well tolerated in all subject groups.
Based on the pharmacokinetic and tolerability findings, no dose adjustment of AZL-M is required for subjects with any degree of renal impairment, including end-stage renal disease.
This study was sponsored by Takeda Global Research and Development Center, Inc. The sponsor designed the study. Dr. Richard Preston, the primary investigator, conducted the study and collected the data. The sponsor and the authors analyzed and interpreted the data. The sponsor wrote the study report. The authors and the sponsor agreed jointly to submit the manuscript for publication. The authors drafted the manuscript and received no medical writing assistance or financial support for its development. The authors thank Mr. R. Eric Schmidt, Mr. Larry Kosobud, and the staff of Covance Laboratories, Madison, WI, USA, for conducting the bioanalytical portion of the study. Caroline Dudkowski and Zhen Zhao are employees of Takeda. Aziz Karim is a former employee of Takeda and held stock options. Richard A. Preston has a consulting agreement with Ferring Inc. Richard A. Preston and Dyal Garg have not received honoraria for speaking and attending meetings. They have received phase I research grants in the last 2 years from Novartis, Celgene, Shionogi USA, Forest Research Institute, Abbott Laboratories, Takeda Global Research and Development, Merck and Celerion. Oliver Lenz has no conflicts of interest that are directly relevant to the content of this study.
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