Clinical Pharmacokinetics

, Volume 52, Issue 5, pp 347–358

Single-Center Evaluation of the Single-Dose Pharmacokinetics of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Renal Impairment

Authors

    • Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of MedicineUniversity of Miami
    • Jackson Memorial Hospital
    • Department of Cellular Biology and Pharmacology, Herbert Wertheim College of MedicineFlorida International University
  • Aziz Karim
    • AzK Consulting Inc.
  • Caroline Dudkowski
    • Takeda Global Research & Development Inc.
  • Zhen Zhao
    • Takeda Global Research & Development Inc.
  • Dyal Garg
    • Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of MedicineUniversity of Miami
    • Clinical Research Services, Inc.
  • Oliver Lenz
    • Division of Nephrology, Department of Medicine, Miller School of MedicineUniversity of Miami
  • Domenic A. Sica
    • Division of Nephrology, Department of MedicineVirginia Commonwealth University School of Medicine
Original Research Article

DOI: 10.1007/s40262-013-0044-y

Cite this article as:
Preston, R.A., Karim, A., Dudkowski, C. et al. Clin Pharmacokinet (2013) 52: 347. doi:10.1007/s40262-013-0044-y

Abstract

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.

Methods

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).

Results

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.

Conclusions

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.

Copyright information

© Springer International Publishing Switzerland 2013