Skip to main content
SpringerLink
Log in

Population pharmacokinetics of bisoprolol in patients with chronic heart failure

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of bisoprolol in patients with congestive heart failure (CHF).

Methods

Parameters associated with the plasma concentrations of bisoprolol at steady-state were analyzed in 61 patients (mean age 66.21 ± 9.49 years; mean total body weight 8.90 ± 12.26 kg) with CHF using non-linear mixed-effect modeling (NONMEM). A validation set of 17 patients with heart failure was used to estimate the predictive performance of the pharmacokinetic model.

Results

The typical mean value for bisoprolol clearance (CL), estimated by the base model (without covariates), in our population was 11.4 l h−1. In the full model, covariates such as bisoprolol total daily dose (DD) and creatinine clearance were included. The final regression model for the clearance of bisoprolol was the following: CL (l h−1) = 4.68 + 0.859 * DD.

Conclusion

The derived PK model describes the clearance of bisoprolol in patients with CHF, showing that the total daily dose of bisoprolol is the most important covariate. This finding will provide the basis for future PK studies on beta blockers in this specific patient population and lead to better overall management of heart failure.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. [No authors listed] (1999) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 353(9146):9–13

    Google Scholar 

  2. Dickstein K, Cohen-Solal A, Filippatos G et al (2008) For the task force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail 10:933–989

    Article  PubMed  Google Scholar 

  3. Borchard U (1990) Pharmacokinetics of beta-adrenoceptor blocking agents: clinical significance of hepatic and/or renal clearance. Clin Physiol Biochem 8[Suppl 2]:28–34

    PubMed  Google Scholar 

  4. Horikiri Y, Suzuki T, Mizobe M (1998) Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci 87(3):289–294

    Article  PubMed  CAS  Google Scholar 

  5. McGavin JK, Keating GM (2002) Bisoprolol: a review of its use in chronic heart failure. Drugs 62(18):2677–2696

    Article  PubMed  CAS  Google Scholar 

  6. Grevel J, Thomas P, Whiting B (1989) Population pharmacokinetic analysis of bisoprolol. Clin Pharmacokinet 17(1):53–63

    Article  PubMed  CAS  Google Scholar 

  7. Zanger UM, Raimundo S, Eichelbaum M (2004) Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol 369:23–37

    Article  PubMed  CAS  Google Scholar 

  8. Bradford LD (2002) CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 3:229–243

    Article  PubMed  CAS  Google Scholar 

  9. Gaedigk A, Simon S, Pearce R, Bradford L, Kennedy M, Leeder J (2008) The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Mol Ther 83:234–242

    Article  CAS  Google Scholar 

  10. Buhring KU, Garbe A (1986) Determination of the new beta-blocker bisoprolol and of metoprolol, atenolol and propranolol in plasma and urine by high-performance liquid chromatography. J Chromatogr 382:215–224

    Article  PubMed  CAS  Google Scholar 

  11. Poirier JM, Perez M, Cheymol G, Jaillon P (1988) Rapid and sensitive high-performance liquid chromatographic determination of bisoprolol in plasma and urine. J Chromatogr 426:431–437

    Article  PubMed  CAS  Google Scholar 

  12. Suzuki T, Horikiri Y, Mizobe M, Noda K (1993) Sensitive determination of bisoprolol enantiomers in plasma and urine by highperformance liquid chromatography using fluorescence detection, and application to preliminary study in humans. J Chromatogr 619:267–273

    Article  PubMed  CAS  Google Scholar 

  13. Beal SL, Sheiner LB (1998) NONMEM Users Guides. NONMEM Project Group, University of San Francisco, San Francisco

  14. Milovanovic JR, Jankovic SM (2011) Factors influencing carbamazepine PK in children and adults: population PK-analysis. Int J Clin Pharmacol Ther 48:428–436

    Google Scholar 

  15. Sheiner LB, Beal SL (1981) Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 9:503–512

    Article  PubMed  CAS  Google Scholar 

  16. Kirch W, Rose I, Klingmann I, Pabst J, Ohnhaus EE (1986) Interaction of bisoprolol with cimetidine and rifampicin. Eur J Clin Pharmacol 31:59–62

    Article  PubMed  CAS  Google Scholar 

  17. Kirch W, Rose I, Demers HG, Leopold G, Pabst J, Ohnhaus EE (1987) Pharmacokinetics of bisoprolol during repeated oral administration to healthy volunteers and patients with kidney or liver disease. Clin Pharmacokinet 13:110–117

    Article  PubMed  CAS  Google Scholar 

  18. Leopold G, Pabst J, Ungethüm W, Bühring KU (1986) Basic pharmacokinetics of bisoprolol, a new highly beta 1-selective adrenoceptor antagonist. J Clin Pharmacol 26:616–621

    Article  PubMed  CAS  Google Scholar 

  19. Taguchi M, Nozawa T, Igawa A, Inoue H, Takesono C, Tahara K, Hashimoto Y (2005) Pharmacokinetic variability of routinely administered bisoprolol in middle-aged and elderly Japanese patients. Biol Pharm Bull 28:876–881

    Article  PubMed  CAS  Google Scholar 

  20. Horikiri Y, Suzuki T, Mizobe M (1998) Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci 63:1097–1108

    Article  PubMed  CAS  Google Scholar 

  21. Nozawa T, Taguchi M, Tahara K, Hashimoto Y, Igarashi N, Nonomura M, Kato B, Igawa A, Inoue H (2005) Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol. J Cardiovasc Pharmacol 46(5):713–720

    Article  PubMed  CAS  Google Scholar 

  22. Rau T, Heide R, Bergmann K et al (2002) Effect of the CYP2D6 genotype on metoprolol metabolism persists during long-term treatment. Pharmacogenetics 12:165–172

    Article  Google Scholar 

  23. Taguchi M, Nozawa T, Kameyama T et al (2003) Effect of CYP2D6*10 on pharmacokinetic variability of routinely administered metoprolol in middle-aged and elderly Japanese patients. Eur J Clin Pharmacol 59:385–388

    Article  PubMed  CAS  Google Scholar 

  24. Giessmann T, Modess C, Hecker U, Zschiesche M, Dazert P, Kunert-Keil C, Warzok R, Engel G, Weitschies W, Cascorbi I, Kroemer HK, Siegmund W (2004) CYP2D6 genotype and induction of intestinal drug transporters by rifampin predict presystemic clearance of carvedilol in healthy subjects. Clin Pharmacol Ther 75:213–222

    Article  PubMed  CAS  Google Scholar 

  25. Bijl MJ, Visser LE, van Schaik RH, Kors JA, Witteman JC, Hofman A, Vulto AG, van Gelder T, Stricker BH (2009) Genetic variation in the CYP2D6 gene is associated with a lower heart rate and blood pressure in beta-blocker users. Clin Pharmacol Ther 85(1):45–50

    Article  PubMed  CAS  Google Scholar 

  26. Rau T, Wuttke H, Michels LM, Werner U, Bergmann K, Kreft M, Fromm MF, Eschenhagen (2009) Impact of the CYP2D6 genotype on the clinical effects of metoprolol: a prospective longitudinal study. Clin Pharmacol Ther 85:269–272

    Article  PubMed  CAS  Google Scholar 

  27. Castagno D, Jhund PS, McMurray JJ, Lewsey JD, Erdmann E, Zannad F, Remme WJ, Lopez-Sendon JL, Lechat P, Follath F, Höglund C, Mareev V, Sadowski Z, Seabra-Gomes RJ, Dargie HJ (2010) Improved survival with bisoprolol in patients with heart failure and renal impairment:an analysis of the cardiac insufficiency bisoprolol study II (CIBIS-II) trial. Eur J Heart Fail 12:607–616

    Article  PubMed  CAS  Google Scholar 

  28. Tahara K, Saigusa K, Kagawa Y, Taguchi M, Hashimoto Y (2006) Pharmacokinetics and pharmacodynamics of bisoprolol in rats with bilateral ureter ligation-induced renal failure. Drug Metab Pharmacokinet 21:389–394

    Article  PubMed  CAS  Google Scholar 

  29. Leopold G (1986) Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol 8(Suppl):S16–S20

    PubMed  CAS  Google Scholar 

  30. Dutta A, Lanc R, Begg E, Robson R, Sia L, Dukart G, Desjardins R, Yacobi A (1994) Dose proportionality of bisoprolol enantiomers in humans after oral administration of the racemate. J Clin Pharmacol 34:829–836

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was partially funded by grant no. 175007 from Serbian Ministry of Education and by grant no. 01-404 given by Ministry of Science of Montenegro.

Author information

Authors and Affiliations

  1. Pharmacology Department, Medical Faculty, University of Nis, Nis, Serbia

    Valentina N. Nikolic & Srdjan Pesic

  2. Pharmacology Department, Medical Faculty, University of Kragujevac, Kragujevac, Serbia

    Dejana Ruzic Zecevic, Jasmina R. Milovanovic & Slobodan M. Jankovic

  3. Institute of Biochemistry, Medical Faculty, University of Nis, Nis, Serbia

    Tatjana Jevtovic-Stoimenov

  4. Department of Pharmacy, Medical Faculty, University of Nis, Nis, Serbia

    Radmila Velickovic-Radovanović & Nikola Stefanovic

  5. Department of Nephrology, Clinical Center Nis, Nis, Serbia

    Radmila Velickovic-Radovanović

  6. Department of Cardiology, Institute of Treatment and Rehabilitation “Niska Banja”, Medical Faculty, University of Nis, Nis, Serbia

    Stevan Ilic & Marina Deljanin-Ilic

  7. Department of Cardiology, Institute of Treatment and Rehabilitation “Niska Banja”, Niska Banja, Serbia

    Dragan Marinkovic

  8. Department of Internal Medicine—Cardiology, Medical Faculty, University of Nis, Nis, Serbia

    Stevan Ilic, Marina Deljanin-Ilic & Svetlana Apostolović

  9. Clinic for Cardiovascular Diseases, Clinical Centre Nis, Nis, Serbia

    Svetlana Apostolović & Dragana Stanojevic

  10. Laboratory for Functional Genomics and Proteomics, Research Center for Biomedicine, Medical Faculty, University of Nis, Nis, Serbia

    Slavoljub Zivanovic

Authors
  1. Valentina N. Nikolic
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatjana Jevtovic-Stoimenov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Radmila Velickovic-Radovanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stevan Ilic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marina Deljanin-Ilic
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dragan Marinkovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Svetlana Apostolović
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dragana Stanojevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Slavoljub Zivanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nikola Stefanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Srdjan Pesic
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dejana Ruzic Zecevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jasmina R. Milovanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Slobodan M. Jankovic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Valentina N. Nikolic.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nikolic, V.N., Jevtovic-Stoimenov, T., Velickovic-Radovanović, R. et al. Population pharmacokinetics of bisoprolol in patients with chronic heart failure. Eur J Clin Pharmacol 69, 859–865 (2013). https://doi.org/10.1007/s00228-012-1427-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1427-y

Keywords

Search

Navigation