title: Single-center evaluation of the single-dose pharmacokinetics of the angiotensin II receptor antagonist azilsartan medoxomil in renal impairment.
abstract: 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.
authors.affiliation: Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of Medicine, University of Miami, 1500 NW 12th Avenue 15 West, Miami, FL, USA. rpreston@med.miami.edu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Preston
authors.forename: Aziz
authors.initials: A
authors.lastname: Karim
authors.forename: Caroline
authors.initials: C
authors.lastname: Dudkowski
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.forename: Dyal
authors.initials: D
authors.lastname: Garg
authors.forename: Oliver
authors.initials: O
authors.lastname: Lenz
authors.forename: Domenic A
authors.initials: DA
authors.lastname: Sica
mesh_terms: D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007676:Kidney Failure, Chronic / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011355:Prodrugs; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000503:physiopathology* / Q000628:therapy; D012720:Severity of Illness Index
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D010069:Oxadiazoles; D011355:Prodrugs; C557413:azilsartan medoxomil