Single-center evaluation of the single-dose pharmacokinetics of the angiotensin ii receptor antagonist azilsartan medoxomil in renal impairment

Richard A Preston, Aziz Karim, Caroline Dudkowski, Zhen Zhao, Dyal Garg, Oliver Lenz, Domenic A. Sica

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)347-358
Number of pages12
JournalClinical Pharmacokinetics
Volume52
Issue number5
DOIs
StatePublished - May 1 2013

Fingerprint

Angiotensin Receptor Antagonists
Pharmacokinetics
Kidney
Chronic Kidney Failure
Renal Dialysis
Prodrugs
azilsartan
azilsartan medoxomil
Protein Binding
Oral Administration
Blood Proteins
Healthy Volunteers
Hydrolysis
Blood Pressure

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Single-center evaluation of the single-dose pharmacokinetics of the angiotensin ii receptor antagonist azilsartan medoxomil in renal impairment. / Preston, Richard A; Karim, Aziz; Dudkowski, Caroline; Zhao, Zhen; Garg, Dyal; Lenz, Oliver; Sica, Domenic A.

In: Clinical Pharmacokinetics, Vol. 52, No. 5, 01.05.2013, p. 347-358.

Research output: Contribution to journalArticle

@article{f289ce7be33a4b238ad7cb7fc429d089,
title = "Single-center evaluation of the single-dose pharmacokinetics of the angiotensin ii receptor antagonist azilsartan medoxomil in renal impairment",
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.",
author = "Preston, {Richard A} and Aziz Karim and Caroline Dudkowski and Zhen Zhao and Dyal Garg and Oliver Lenz and Sica, {Domenic A.}",
year = "2013",
month = "5",
day = "1",
doi = "10.1007/s40262-013-0044-y",
language = "English",
volume = "52",
pages = "347--358",
journal = "Clinical Pharmacokinetics",
issn = "0312-5963",
publisher = "Adis International Ltd",
number = "5",

}

TY - JOUR

T1 - Single-center evaluation of the single-dose pharmacokinetics of the angiotensin ii receptor antagonist azilsartan medoxomil in renal impairment

AU - Preston, Richard A

AU - Karim, Aziz

AU - Dudkowski, Caroline

AU - Zhao, Zhen

AU - Garg, Dyal

AU - Lenz, Oliver

AU - Sica, Domenic A.

PY - 2013/5/1

Y1 - 2013/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885594586&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885594586&partnerID=8YFLogxK

U2 - 10.1007/s40262-013-0044-y

DO - 10.1007/s40262-013-0044-y

M3 - Article

C2 - 23575872

AN - SCOPUS:84885594586

VL - 52

SP - 347

EP - 358

JO - Clinical Pharmacokinetics

JF - Clinical Pharmacokinetics

SN - 0312-5963

IS - 5

ER -