Clinical Pharmacokinetics

, Volume 52, Issue 5, pp 347–358 | Cite as

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
Original Research Article

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.

Notes

Acknowledgments

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.

References

  1. 1.
    Sica DA. The pharmacology of agents that interfere with renin-angiotensin system activity. J Renin Angiotensin Aldosterone System. 2006;7:247–50.CrossRefGoogle Scholar
  2. 2.
    Dahlof B, Devereux RB, Kjeldsen SE, LIFE Study Group, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003.PubMedCrossRefGoogle Scholar
  3. 3.
    Pfeffer MA, Swedberg K, Granger CB, CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall Programme. Lancet. 2003;362:759–66.PubMedCrossRefGoogle Scholar
  4. 4.
    Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–75.PubMedCrossRefGoogle Scholar
  5. 5.
    Solomon SD, Wang D, Finn P, et al. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation. 2004;110:2180–3.PubMedCrossRefGoogle Scholar
  6. 6.
    Lindholm LH, Dahlof B, Edelman JM, LIFE study group, et al. Effect of losartan on sudden cardiac death in people with diabetes: data from the LIFE study. Lancet. 2003;362:619–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Yusuf S, Teo K, Anderson C, Telmisartan Randomised Assessment Study in ACE-Intolerant Subjects with Cardiovascular Disease (TRANSCEND) investigators, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372:1174–83.PubMedCrossRefGoogle Scholar
  8. 8.
    Yusuf S, Diener HC, Sacco RL, PRoFESS Study Group, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359:1225–37.PubMedCrossRefGoogle Scholar
  9. 9.
    Demers C, McMurray JJV, Swedberg K, CHARM Investigators, et al. Impact of candesartan on nonfatal myocardial infarction and cardiovascular death in patients with heart failure. JAMA. 2005;294:1794–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:1004–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Solomon SD, Wang D, Finn P, et al. Effect of candesartan on cause-specific mortality in heart failure patients: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) Program. Circulation. 2004;110:2180–3.PubMedCrossRefGoogle Scholar
  12. 12.
    Brenner BM, Cooper ME, de Zeeuw D, RENAAL Study Investigators, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Lewis EJ, Hunsicker LG, Clarke WR, Collaborative Study Group, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.PubMedCrossRefGoogle Scholar
  14. 14.
    Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P, Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Bakris GL, Sica D, Weber M, et al. The comparative effects of azilsartan medoxomil and olmesartan on ambulatory and clinic blood pressure. J Clin Hypertens (Greenwich). 2011;13:81–8.CrossRefGoogle Scholar
  16. 16.
    White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011;57:413–20.PubMedCrossRefGoogle Scholar
  17. 17.
    Sica D, White WB, Weber MA, et al. Comparison of the novel angiotensin II receptor blocker azilsartan medoxomil vs valsartan by ambulatory blood pressure monitoring. J Clin Hypertens (Greenwich). 2011;13:467–72.CrossRefGoogle Scholar
  18. 18.
    Takeda Global Research & Development Center. Global Investigator’s Brochure. TAK-491. Azilsartan medoxomil. Edition 5.0. Takeda Global Research & Development Center, Inc., Deerfield; 2008.Google Scholar
  19. 19.
    Takeda Global Research & Development Center. A phase 1, open-label mass balance and excretion study of [14C] TAK-491 following oral administration in healthy male subjects. Report No. 01-06-TL-491-012. Deerfield: Takeda Global Research & Development Center, Inc. 2007.Google Scholar
  20. 20.
    Takeda Pharmaceuticals America. Edarbi [prescribing information]. http://www.edarbi.com/. Accessed 8 Nov 2012.
  21. 21.
    Preston RA, Karim A, Garg D, et al. Single-center phase I study of the single- and multiple-dose pharmacokinetics and safety of azilsartan medoxomil (AZL-M) in hepatic impairment (abstract no. PII-99). Clin Pharmacol Ther. 2012;91(Suppl 1):S89.Google Scholar
  22. 22.
    Harrell R, Karim A, Zhang W, et al. Effects of age, gender, and race on the safety and pharmacokinetics of single and multiple doses of azilsartan medoxomil in healthy subjects (abstract no. PII-69). Clin Pharmacol Ther 2012;91(Suppl 1):S78.Google Scholar
  23. 23.
    Kajiya T, Ho C, Wang J, Vilarbi R, Kurtz TW. Molecular and cellular effects of azilsartan: a new generation angiotensin II receptor blocker. J Hypertension. 2011;29:2476–83.CrossRefGoogle Scholar
  24. 24.
    Baker WL, White WB. Azilsartan medoxomil: a new angiotensin II receptor antagonist for treatment of hypertension. Ann Pharmacother. 2011;45:1506–15.PubMedCrossRefGoogle Scholar
  25. 25.
    Perry C. Azilsartan medoxomil. A review of its use in hypertension. Clin Drug Investig. 2012;32:621–39.PubMedGoogle Scholar
  26. 26.
    Zaiken K, Cheng JWM. Azilsartan medoxomil: a new angiotensin II receptor blocker. Clin Ther. 2011;33:1577–89.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  • Richard A. Preston
    • 1
    • 2
    • 3
  • Aziz Karim
    • 4
  • Caroline Dudkowski
    • 5
  • Zhen Zhao
    • 5
  • Dyal Garg
    • 1
    • 6
  • Oliver Lenz
    • 7
  • Domenic A. Sica
    • 8
  1. 1.Clinical Pharmacology Research Unit, Division of Clinical Pharmacology, Department of Medicine, Miller School of MedicineUniversity of MiamiMiamiUSA
  2. 2.Jackson Memorial HospitalMiamiUSA
  3. 3.Department of Cellular Biology and Pharmacology, Herbert Wertheim College of MedicineFlorida International UniversityMiamiUSA
  4. 4.AzK Consulting Inc.SkokieUSA
  5. 5.Takeda Global Research & Development Inc.DeerfieldUSA
  6. 6.Clinical Research Services, Inc.Boynton BeachUSA
  7. 7.Division of Nephrology, Department of Medicine, Miller School of MedicineUniversity of MiamiMiamiUSA
  8. 8.Division of Nephrology, Department of MedicineVirginia Commonwealth University School of MedicineRichmondUSA

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