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Effect of Severe Renal Failure and Haemodialysis on the Pharmacokinetics of Levosimendan and Its Metabolites

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Abstract

Background and objectives

Levosimendan is a calcium sensitiser developed for the treatment of congestive heart failure. It increases myocardial contractility, reduces the filling pressure and dilates both the peripheral and coronary vessels. The circulating metabolites of levosimendan, OR-1855 and OR-1896, are formed and eliminated slowly after intravenous administration of levosimendan. The aim of this study was to investigate the effect of impaired renal function and haemodialysis on the pharmacokinetics of levosimendan, OR-1855 and OR-1896.

Study design

This study was an open-label, nonrandomised, phase I pharmacokinetic study. Levosimendan was administered as a single-dose infusion of 0.1 μg/kg/minute for 24 hours. The follow-up period lasted 3 weeks.

Study setting

Twenty-five patients were included: 12 patients with severe chronic renal failure (CRF) with creatinine clearance of <30 mL/minute/1.73m2 and 13 patients with end-stage renal disease (ESRD) undergoing haemodialysis. A group of 12 healthy subjects served as controls.

Results

Levosimendan, the parent drug, was eliminated rapidly from the plasma after discontinuation of its infusion, with an elimination half-life (t½) [mean ±standard error of mean] of 1.5 ± 0.09 hours in ESRD patients undergoing haemodialysis, 1.0 ± 0.2 hours in patients with severe CRF and 0.91 ± 0.03 hours in healthy subjects. The t½ of levosimendan was significantly longer (p < 0.001) in ESRD patients undergoing haemodialysis than in healthy subjects. The t½ of OR-1855 and OR-1896 were 94.0 ± 20.4 hours and 96.5 ± 19.5 hours, respectively, in ESRD patients undergoing haemodialysis compared with 60.8 ± 5.2 and 61.6 ± 5.2 hours, respectively, in healthy subjects (p = not significant). The t½ of OR-1855 was significantly longer (85.0 ± 13.6 hours) in patients with severe CRF than in healthy subjects (60.8 ± 5.2 hours, p < 0.05). The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (Cmax) of the metabolites were approximately 2-fold higher in patients with ESRD undergoing haemodialysis and patients with severe CRF compared with healthy subjects. The mean unbound fraction (fu) of levosimendan in plasma was approximately 2% in each study group, whereas the fu of the metabolites was considerably higher (63−70%). In contrast to levosimendan, the metabolites were dialysable, with dialysis clearance of approximately 100 mL/minute. The haemodynamic responses and adverse event profiles were similar in the study groups, with headache, palpitations and dizziness being the most frequently recorded adverse events.

Conclusion

The t½ of the levosimendan metabolites was prolonged 1.5-fold and their AUC and Cmax were 2-fold higher in patients with severe CRF and ESRD patients undergoing haemodialysis as compared with healthy subjects. These results suggest that the dose should be reduced when levosimendan is used for the treatment of congestive heart failure in patients with severe renal insufficiency.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

This study was funded by Orion Pharma. All authors, with the exception of Veli-Pekka Harjola, Petri Koskinen and Pertti J Pentikäinen, are employees of Orion Pharma. The authors acknowledge the nursing and technical staff at Helsinki University Central Hospital (Helsinki, Finland) and APEX Research (Munich, Germany), and the laboratory staff at Orion Pharma (Espoo, Finland). The authors would also like to thank Sirpa Laakso, MSc, for performing the protein-binding analysis and Drs Wenhui Zhang and Rajendra Pradham (Abbott, Chicago, IL, USA) for their valuable comments on the manuscript.

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Authors and Affiliations

  1. Clinical R&D, Orion Pharma, P.O. Box 1780, Kuopio, FI-70701, Finland

    Jaakko Puttonen

  2. Department of Biostatistics and Data Management, R&D, Orion Pharma, Espoo, Finland

    Sampo Kantete

  3. Clinical R&D, Orion Pharma, Espoo, Finland

    Matti Kivikko

  4. Non-Clinical R&D, Orion Pharma, Espoo, Finland

    Sari Häkkinen

  5. Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    Veli-Pekka Harjola & Pertti J. Pentikäinen

  6. Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland

    Petri Koskinen

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  1. Jaakko Puttonen
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Correspondence to Jaakko Puttonen.

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Puttonen, J., Kantete, S., Kivikko, M. et al. Effect of Severe Renal Failure and Haemodialysis on the Pharmacokinetics of Levosimendan and Its Metabolites. Clin Pharmacokinet 46, 235–246 (2007). https://doi.org/10.2165/00003088-200746030-00004

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