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

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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.

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References

  1. Sica DA. The pharmacology of agents that interfere with renin-angiotensin system activity. J Renin Angiotensin Aldosterone System. 2006;7:247–50.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

  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.

  20. Takeda Pharmaceuticals America. Edarbi [prescribing information]. http://www.edarbi.com/. Accessed 8 Nov 2012.

  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. 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. 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.

    Article  CAS  Google Scholar 

  24. Baker WL, White WB. Azilsartan medoxomil: a new angiotensin II receptor antagonist for treatment of hypertension. Ann Pharmacother. 2011;45:1506–15.

    Article  PubMed  CAS  Google Scholar 

  25. Perry C. Azilsartan medoxomil. A review of its use in hypertension. Clin Drug Investig. 2012;32:621–39.

    PubMed  CAS  Google Scholar 

  26. Zaiken K, Cheng JWM. Azilsartan medoxomil: a new angiotensin II receptor blocker. Clin Ther. 2011;33:1577–89.

    Article  PubMed  CAS  Google Scholar 

Download references

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.

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Authors and Affiliations

  1. 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

    Richard A. Preston & Dyal Garg

  2. Jackson Memorial Hospital, Miami, FL, USA

    Richard A. Preston

  3. Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA

    Richard A. Preston

  4. AzK Consulting Inc., Skokie, IL, USA

    Aziz Karim

  5. Takeda Global Research & Development Inc., Deerfield, IL, USA

    Caroline Dudkowski & Zhen Zhao

  6. Clinical Research Services, Inc., Boynton Beach, FL, USA

    Dyal Garg

  7. Division of Nephrology, Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL, USA

    Oliver Lenz

  8. Division of Nephrology, Department of Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Domenic A. Sica

Authors
  1. Richard A. Preston
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  2. Aziz Karim
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  3. Caroline Dudkowski
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  4. Zhen Zhao
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  5. Dyal Garg
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  6. Oliver Lenz
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  7. Domenic A. Sica
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Corresponding author

Correspondence to Richard A. Preston.

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Preston, R.A., Karim, A., Dudkowski, C. et al. Single-Center Evaluation of the Single-Dose Pharmacokinetics of the Angiotensin II Receptor Antagonist Azilsartan Medoxomil in Renal Impairment. Clin Pharmacokinet 52, 347–358 (2013). https://doi.org/10.1007/s40262-013-0044-y

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  • DOI: https://doi.org/10.1007/s40262-013-0044-y

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