Advertisement

Clinical Drug Investigation

, Volume 33, Issue 1, pp 11–23 | Cite as

Effect of Renal or Hepatic Impairment on the Pharmacokinetics of Mirabegron

  • James Dickinson
  • Michaelene Lewand
  • Taiji Sawamoto
  • Walter Krauwinkel
  • Marloes Schaddelee
  • James Keirns
  • Virginie Kerbusch
  • Selina Moy
  • John Meijer
  • Donna Kowalski
  • Richard Morton
  • Kenneth Lasseter
  • Dennis Riff
  • Viera Kupčová
  • Marcel van GelderenEmail author
Original Research Article

Abstract

Background and Objectives

Mirabegron, a selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), is eliminated by renal and metabolic routes. The potential influence of renal or hepatic impairment on the pharmacokinetics of mirabegron was evaluated.

Methods

Two separate open-label, single-dose, parallel-group studies were conducted. Male and female subjects (n = 8 per group) were categorized according to their baseline renal function (mild, moderate, severe or no impairment as determined by estimated glomerular filtration rate [eGFR] using the abbreviated modification of diet in renal disease formula) or hepatic function (mild, moderate or no impairment as determined by the Child-Pugh classification). All subjects received a single oral 100 mg dose of mirabegron. Non-compartmental pharmacokinetic parameters were determined from plasma and urine concentration-time data of mirabegron and metabolites.

Results

Compared with healthy subjects who were similar overall in terms of age, sex and body mass index (BMI), the geometric mean area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC) for mirabegron was 31, 66 and 118 % higher in subjects with mild, moderate and severe renal impairment, respectively. Peak plasma concentrations (Cmax) increased 6, 23 and 92 %, respectively, in subjects with mild, moderate and severe renal impairment. Renal clearance but not apparent total body clearance of mirabegron correlated well with renal function. Compared with healthy subjects matched for age, sex and BMI, mirabegron AUC values were 19 and 65 % higher in subjects with mild and moderate hepatic impairment, respectively. Mirabegron Cmax was 9 and 175 % higher, respectively, compared with matched healthy subjects. No clear relationship was evident between pharmacokinetic parameters and Child-Pugh scores. Protein binding was approximately 71 % in healthy subjects and was not altered to a clinically significant extent in subjects with renal or hepatic impairment. No consistent changes in mirabegron elimination half-life were observed in subjects with renal or hepatic impairment. There was high pharmacokinetic variability and significant overlap in exposures between subjects with renal or hepatic impairment and healthy subjects.

Conclusion

Mirabegron AUC and Cmax increased 118 and 92 %, respectively, in subjects with severe renal impairment, and 65 and 175 %, respectively, in subjects with moderate hepatic impairment. Pharmacokinetic changes observed in subjects with mild or moderate renal impairment or mild hepatic impairment are of small magnitude and likely to be without clinical importance.

Keywords

Renal Impairment Hepatic Impairment Severe Renal Impairment Mirabegron Moderate Hepatic Impairment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

These studies were supported financially by Astellas. Astellas was responsible for the design and overall management of the studies, and the collection, analysis and interpretation of data. James Dickinson, Michaelene Lewand, Taiji Sawamoto, Walter Krauwinkel, Marloes Schaddelee, James Keirns, Selina Moy, John Meijer, Donna Kowalski and Marcel van Gelderen are employees of Astellas. Virginie Kerbusch (PharmAspire Consulting) participated in the analysis and interpretation of the data and writing of the reports and drafted the manuscript, funded by Astellas. Richard Morton (external consultant statistician) performed the statistical analysis of the hepatic impairment study, which was funded by Astellas. Kenneth Lasseter, Dennis Riff and Viera Kupčová were the principal investigators for the studies and have no conflicts of interest to declare. All authors listed were involved in critical review and revision of the manuscript, and all provided final approval of the content.

References

  1. 1.
    Takasu T, Ukai M, Sato S, et al. Effect of (R)-2-(2-aminothiazol-4-yl)-4’-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective β3-adrenoceptor agonist, on bladder function. J Pharmacol Exp Ther. 2007;321(2):642–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Wein AJ, Rovner ES. Definition and epidemiology of overactive bladder. Urology. 2002;60(5 Suppl 1):7–12.PubMedCrossRefGoogle Scholar
  3. 3.
    Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21:167–78.PubMedCrossRefGoogle Scholar
  4. 4.
    Athanasopoulos A, Giannitsas K. An overview of the clinical use of antimuscarinics in the treatment of overactive bladder. Adv Urol. 2011;2011:820816.PubMedCrossRefGoogle Scholar
  5. 5.
    Khullar V, Amarenco G, Angulo J, et al. Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder: results from a randomized European–Australian Phase 3 trial. Eur Urol. Accepted.Google Scholar
  6. 6.
    Nitti V, Auerbach S, Martin N, et al. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol. 2012. doi: 10.1016/j.juro.2012.10.017. (Epub ahead of print).
  7. 7.
    Takusagawa S, van Lier JJ, Suzuki K, et al. Absorption, metabolism and excretion of [14C]mirabegron (YM178), a potent and selective β3-adrenoceptor agonist, after oral administration to healthy male volunteers. Drug Metab Dispos. 2012;40(4):815–24.PubMedCrossRefGoogle Scholar
  8. 8.
    Takusagawa S, Yajima K, Miyashita A, et al. Identification of human cytochrome P450 isoforms and esterases involved in the metabolism of mirabegron (YM178), a potent and selective β3-adrenoceptor agonist. Xenobiotica. 2012;42(10):957–67. doi: 10.3109/00498254.00492012.00675095.PubMedCrossRefGoogle Scholar
  9. 9.
    Sawamoto T, Lee J, Alak A, et al. Phase I, open-label, drug interaction study to evaluate the effect of multiple doses of ketoconazole on single dose mirabegron (YM178) oral controlled absorption system (OCAS) in healthy adult subjects. Clin Pharmacol Ther. 2011;89(suppl. 1):S21. Abstr. PI-43.Google Scholar
  10. 10.
    van Gelderen E, Li Q, Meijer J, et al. An exploratory comparison of the single dose pharmacokinetics of the β3-adrenoceptor agonist mirabegron in healthy CYP2D6 poor and extensive metabolizers. Clin Pharmacol Ther. 2009;85(Suppl 1):S88.Google Scholar
  11. 11.
    Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Stevens LA, Coresh J, Greene T, et al. Assessing kidney function-measured and estimated glomerular filtration rate. N Engl J Med. 2006;354(23):2473–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.PubMedCrossRefGoogle Scholar
  14. 14.
    Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Center for Drug Evaluation and Research (CDER). Guidance for industry. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. 2003. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072123.pdf. Accessed 7 Feb 2012.
  16. 16.
    Center for Drug Evaluation and Research (CDER). Draft guidance for industry. Pharmacokinetics in patients with impaired renal function: study design, data analysis, and impact on dosing and labeling (revision 1). 2010. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM204959.pdf. Accessed 7 Feb 2012.
  17. 17.
    Committee for Medicinal Products for Human Use (CHMP) European Medicines Agency. Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function (reference no. CHMP/EWP/225/02). 2004 Jun 23. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003123.pdf. Accessed 7 Feb 2012.
  18. 18.
    Committee for Medicinal Products for Human Use (CHMP) European Medicines Agency. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function (reference no. CPMP/EWP/2339/02). 2005 Feb 17. http://www.tga.gov.au/pdf/euguide/ewp233902en.pdf. Accessed 7 Feb 2012.
  19. 19.
    van Teijlingen R, Meijer J, Takusagawa S, et al. Development and validation of LC-MS/MS methods for the determination of mirabegron and its metabolites in human plasma and their application to a clinical pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;887–888:102–11.PubMedGoogle Scholar
  20. 20.
    Eltink C, Lee J, Schaddelee M, et al. Single dose pharmacokinetics and absolute bioavailability of mirabegron, a selective and potent β3-adrenoceptor agonist for treatment of overactive bladder, in healthy subjects. Int J Clin Pharmacol Ther. 2012;50(11):838–50.PubMedGoogle Scholar
  21. 21.
    Dreisbach AW. The influence of chronic renal failure on drug metabolism and transport. Clin Pharmacol Ther. 2009;86(5):553–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Nolin TD, Naud J, Leblond FA, et al. Emerging evidence of the impact of kidney disease on drug metabolism and transport. Clin Pharmacol Ther. 2008;83(6):898–903.PubMedCrossRefGoogle Scholar
  23. 23.
    Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109(1–2):1–11.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang Y, Zhang L, Abraham S, et al. Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications. Clin Pharmacol Ther. 2009;85(3):305–11.PubMedCrossRefGoogle Scholar
  25. 25.
    Data on file: Takusagawa S. Estimation of the major human plasma binding protein for YM178. Astellas Pharma Inc, Tokyo, Japan, 2004.Google Scholar
  26. 26.
    Data on file: Watanabe M, Ukai M, Ohtake A, et al. Agonist activities of YM178 and its metabolites for human Beta1- Beta2- or Beta3-adrenoceptors expressed in CHO cells. Astellas Pharma Inc, Tsukuba, Japan, 2007.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • James Dickinson
    • 1
  • Michaelene Lewand
    • 2
  • Taiji Sawamoto
    • 2
  • Walter Krauwinkel
    • 1
  • Marloes Schaddelee
    • 1
  • James Keirns
    • 2
  • Virginie Kerbusch
    • 3
  • Selina Moy
    • 2
  • John Meijer
    • 1
  • Donna Kowalski
    • 2
  • Richard Morton
    • 4
  • Kenneth Lasseter
    • 5
  • Dennis Riff
    • 6
  • Viera Kupčová
    • 7
  • Marcel van Gelderen
    • 1
    Email author
  1. 1.Astellas Pharma EuropeGlobal Clinical Pharmacology Exploratory DevelopmentLeiderdorpThe Netherlands
  2. 2.Astellas Pharma Global Development Inc.NorthbrookUSA
  3. 3.PharmAspire ConsultingWijchenThe Netherlands
  4. 4.Independent StatisticianDoncasterUK
  5. 5.Clinical Pharmacology of Miami, Inc.MiamiUSA
  6. 6.Advanced Clinical Research InstituteCAUSA
  7. 7.University Hospital BratislavaBratislavaSlovakia

Personalised recommendations