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Efficacy of Tolvaptan Added to Furosemide in Heart Failure Patients with Advanced Kidney Dysfunction: A Pharmacokinetic and Pharmacodynamic Study

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Abstract

Background and Objectives

The pharmacokinetics and pharmacodynamics of tolvaptan (7.5 or 15 mg/day) in combination with furosemide have been investigated in heart failure (HF) patients with normal kidney function but not in HF patients with advanced kidney dysfunction. This study evaluated the efficacy of tolvaptan in HF patients with advanced kidney dysfunction (estimated glomerular filtration rate <45 mL/min/1.73 m2) by conducting a pharmacokinetic and pharmacodynamic study in these patients.

Methods

Tolvaptan (15 mg once daily) was administered orally for 7 days in combination with furosemide (40–200 mg).

Results

The peak plasma tolvaptan concentration and area under the plasma concentration–time curve were 379.41 ± 149.69 ng/mL and 4,657.38 ± 2,741.79 ng·h/mL, respectively, in HF patients with advanced kidney dysfunction. These values were greater in HF patients with advanced kidney dysfunction than values reported in the literature for healthy subjects and HF patients with normal kidney function. Urine volume increased and body weight decreased significantly compared with those before tolvaptan administration in HF patients with advanced kidney dysfunction.

Conclusion

This study showed that adding tolvaptan to furosemide was effective in HF patients with advanced kidney dysfunction. This study also suggests that in these patients 15 mg/day of tolvaptan should be sufficient, and increasing the dose or the frequency of dosing to overcome diuretic resistance should not be necessary, and consideration should be given to using a lower dose and/or prolonging the dosing interval.

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References

  1. von Lueder TG, Atar D, Krum H. Diuretic use in heart failure and outcomes. Clin Pharmacol Ther. 2013;94(4):490–8.

    Article  Google Scholar 

  2. Hamaguchi S, Tsuchihashi-Makaya M, Kinugawa S, Yokota T, Ide T, Takeshita A, et al. Chronic kidney disease as an independent risk for long-term adverse outcomes in patients hospitalized with heart failure in Japan. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J. 2009;73(8):1442–7.

    Article  PubMed  Google Scholar 

  3. Eshaghian S, Horwich TB, Fonarow GC. Relation of loop diuretic dose to mortality in advanced heart failure. Am J Cardiol. 2006;97(12):1759–64.

    Article  CAS  PubMed  Google Scholar 

  4. Hasselblad V, Gattis Stough W, Shah MR, Lokhnygina Y, O’Connor CM, Califf RM, et al. Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur J Heart Fail. 2007;9(10):1064–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation. 1999;100(12):1311–5.

    Article  CAS  PubMed  Google Scholar 

  6. Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther. 1998;287(3):860–7.

    CAS  PubMed  Google Scholar 

  7. Miyazaki T, Fujiki H, Yamamura Y, Nakamura S, Mori T. Tolvaptan, an orally active vasopressin V(2)-receptor antagonist—pharmacology and clinical trials. Cardiovasc Drug Rev. 2007;25(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  8. Gheorghiade M, Gattis WA, O’Connor CM, Adams KF Jr, Elkayam U, Barbagelata A, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004;291(16):1963–71.

    Article  CAS  PubMed  Google Scholar 

  9. Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007;297(12):1319–31.

    Article  CAS  PubMed  Google Scholar 

  10. Inomata T, Izumi T, Matsuzaki M, Hori M, Hirayama A. Phase III clinical pharmacology study of tolvaptan. Cardiovasc Drugs Ther. 2011;25(Suppl 1):S57–65.

    Article  PubMed  Google Scholar 

  11. Heywood JT, Fonarow GC, Costanzo MR, Mathur VS, Wigneswaran JR, Wynne J. High prevalence of renal dysfunction and its impact on outcome in 118,465 patients hospitalized with acute decompensated heart failure: a report from the ADHERE database. J Card Fail. 2007;13(6):422–30.

    Article  PubMed  Google Scholar 

  12. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787–847.

    Article  PubMed  Google Scholar 

  13. Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80(1):17–28.

    Article  PubMed  Google Scholar 

  14. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53(6):982–92.

    Article  CAS  PubMed  Google Scholar 

  15. Shoaf SE, Kim SR, Bricmont P, Mallikaarjun S. Pharmacokinetics and pharmacodynamics of single-dose oral tolvaptan in fasted and non-fasted states in healthy Caucasian and Japanese male subjects. Eur J Clin Pharmacol. 2012;68(12):1595–603.

    Article  CAS  PubMed  Google Scholar 

  16. Kim SR, Hasunuma T, Sato O, Okada T, Kondo M, Azuma J. Pharmacokinetics, pharmacodynamics and safety of tolvaptan, a novel, oral, selective nonpeptide AVP V2-receptor antagonist: results of single- and multiple-dose studies in healthy Japanese male volunteers. Cardiovasc Drugs Ther. 2011;25(Suppl 1):S5–17.

    Article  PubMed  Google Scholar 

  17. Shoaf SE, Elizari MV, Wang Z, Sekar K, Grinfeld LR, Barbagelata NA, et al. Tolvaptan administration does not affect steady state amiodarone concentrations in patients with cardiac arrhythmias. J Cardiovasc Pharmacol Ther. 2005;10(3):165–71.

    Article  CAS  PubMed  Google Scholar 

  18. Dreisbach AW, Lertora JJ. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol. 2008;4(8):1065–74.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Imamura T, Kinugawa K, Shiga T, Kato N, Muraoka H, Minatsuki S, et al. Novel criteria of urine osmolality effectively predict response to tolvaptan in decompensated heart failure patients–association between non-responders and chronic kidney disease. Circ J. 2013;77(2):397–404.

    Article  CAS  PubMed  Google Scholar 

  20. Kinugawa K, Sato N, Inomata T, Shimakawa T, Iwatake N, Mizuguchi K. Efficacy and safety of tolvaptan in heart failure patients with volume overload. Circ J. 2014;78(4):844–52.

    CAS  PubMed  Google Scholar 

  21. Matsue Y, Suzuki M, Seya M, Iwatsuka R, Mizukami A, Nagahori W, et al. Tolvaptan reduces the risk of worsening renal function in patients with acute decompensated heart failure in high-risk population. J Cardiol. 2013;61(2):169–74.

    Article  PubMed  Google Scholar 

  22. Vaduganathan M, Gheorghiade M, Pang PS, Konstam MA, Zannad F, Swedberg K, et al. Efficacy of oral tolvaptan in acute heart failure patients with hypotension and renal impairment. J Cardiovasc Med (Hagerstown). 2012;13(7):415–22.

    Article  CAS  Google Scholar 

  23. Francis GS, Benedict C, Johnstone DE, Kirlin PC, Nicklas J, Liang CS, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the studies of left ventricular dysfunction (SOLVD). Circulation. 1990;82(5):1724–9.

    Article  CAS  PubMed  Google Scholar 

  24. Costello-Boerrigter LC, Smith WB, Boerrigter G, Ouyang J, Zimmer CA, Orlandi C, et al. Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol. 2006;290(2):F273–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Kinugawa K, Imamura T, Komuro I. Experience of a vasopressin receptor antagonist, tolvaptan under the unique indication in Japanese heart failure patients. Clin Pharmacol Ther. 2013;94(4):449–51.

    Article  CAS  PubMed  Google Scholar 

  26. Watanabe K, Dohi K, Sugimoto T, Yamada T, Sato Y, Ichikawa K, et al. Short-term effects of low-dose tolvaptan on hemodynamic parameters in patients with chronic heart failure. J Cardiol. 2012;60(6):462–9.

    Article  PubMed  Google Scholar 

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Acknowledgments

We would like to thank the staff of the Heart Center, Kidney Center, and the Heart Failure Team at the St. Marianna University School of Medicine Hospital for their help in patient recruitment and data acquisition.

Conflict of interest/Disclosure

Payment for lectures: Keisuke Kida (Otsuka Pharmaceutical Co., Ltd.), Yugo Shibagaki (Otsuka Pharmaceutical Co., Ltd.), Naoto Tominaga (Otsuka Pharmaceutical Co., Ltd.). Research funding: Yoshihiro J. Akashi (Otsuka Pharmaceutical Co., Ltd.), Fumihiko Miyake (Otsuka Pharmaceutical Co., Ltd.), Kenjiro Kimura (Otsuka Pharmaceutical Co., Ltd.).

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Authors and Affiliations

  1. Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan

    Keisuke Kida, Yoshihiro J. Akashi & Fumihiko Miyake

  2. Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan

    Yugo Shibagaki, Naoto Tominaga & Kenjiro Kimura

  3. Department of Pharmacology, St. Marianna University School of Medicine, Kawasaki, Japan

    Naoki Matsumoto

  4. Department of Cardiology, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae, Kawasaki, Kanagawa, 216-8511, Japan

    Keisuke Kida

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  1. Keisuke Kida
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  2. Yugo Shibagaki
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Correspondence to Keisuke Kida.

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Kida, K., Shibagaki, Y., Tominaga, N. et al. Efficacy of Tolvaptan Added to Furosemide in Heart Failure Patients with Advanced Kidney Dysfunction: A Pharmacokinetic and Pharmacodynamic Study. Clin Pharmacokinet 54, 273–284 (2015). https://doi.org/10.1007/s40262-014-0194-6

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  • DOI: https://doi.org/10.1007/s40262-014-0194-6

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