Advertisement

Journal of Gastroenterology

, Volume 45, Issue 9, pp 979–987 | Cite as

A multicenter, open-label, dose-ranging study to exploratively evaluate the efficacy, safety, and dose–response of tolvaptan in patients with decompensated liver cirrhosis

  • Kiwamu OkitaEmail author
  • Isao Sakaida
  • Mitsuru Okada
  • Akira Kaneko
  • Kazuaki Chayama
  • Michio Kato
  • Michio Sata
  • Naomasa Yoshihara
  • Noriyuki Ono
  • Yoshikazu Murawaki
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Objectives

We examined the efficacy of tolvaptan, an orally effective nonpeptide vasopressin V2 receptor antagonist, in a Japanese clinical study in patients with intractable ascites and/or lower limb edema associated with decompensated liver cirrhosis.

Methods

Tolvaptan was orally administrated at titrated doses of 15, 30, and 60 mg once daily after breakfast for 3 days at each dose to 18 liver cirrhosis patients with persistent ascites and/or lower limb edema despite receiving oral furosemide at 40 mg/day or higher.

Results

Decreased body weight and abdominal circumference and improvement of ascites and edema were observed following tolvaptan administration beginning from 15 mg. Composite ascites/edema improvement rate was 88.2% at individual maximum doses and 64.7, 80.0, and 90.9%, respectively, after 3-day administration at 15, 30, and 60 mg. Changes in body weight after 3-day administration at 15, 30, and 60 mg were −1.6 ± 0.9, −2.6 ± 1.2, and −3.4 ± 2.1 kg (mean ± SD), respectively, and decreases of 1 kg or more were seen from day 2 (24 h after first dosing). Changes in abdominal circumference ranged from −2.8 to −6.0 cm. Cumulative 24-h urine volumes after 3-day administration at 15, 30, and 60 mg were, respectively, 3240.3 ± 1014.5, 3943.3 ± 1060.6, and 4537.4 ± 1621.3 mL/day (mean ± SD). Urine osmolarity was markedly decreased and remained decreased until the end of treatment.

Conclusion

Tolvaptan dose-dependently decreased body weight and abdominal circumference and improved ascites and edema beginning from 15 mg, demonstrating a potent aquaretic effect.

Keywords

Tolvaptan (OPC-41061) Vasopressin V2 receptor antagonist Decompensated liver cirrhosis Intractable ascites Leg edema 

Notes

Acknowledgments

The authors are most grateful to their fellow researchers and hospitals for their contribution to data collection.

References

  1. 1.
    Guyton AC, Hall JE. Textbook of medical physiology. 10th ed. Philadelphia, PA: WB Saunders Company; 2000. p. 855–6.Google Scholar
  2. 2.
    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.PubMedGoogle Scholar
  3. 3.
    Doggrell SA. Tolvaptan (Otsuka). Curr Opin Investig Drugs. 2004;5:977–83.PubMedGoogle Scholar
  4. 4.
    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;290:273–8.CrossRefGoogle Scholar
  5. 5.
    Lieberman FL, Ito S, Reynolds TB. Effective plasma volume in cirrhosis with ascites. Evidence that a decreased value does not account for renal sodium retention, a spontaneous reduction in glomerular filtration rate (GFR), a fall in GFR during drug-induced diuresis. J Clin Invest. 1969;48(6):975–81.CrossRefPubMedGoogle Scholar
  6. 6.
    Lieberman FL, Denison EK, Reynolds TB. The relationship of plasma volume, portal hypertension, ascites, and renal sodium retention in cirrhosis: the “overflow” theory of ascites formation. Ann NY Acad Sci. 1970;170:202–6.CrossRefGoogle Scholar
  7. 7.
    Levy M. Pathophysiology of ascites formation. In: Epstein M, editor. The kidney in liver disease. 2nd ed. New York: Elsevier, 1982. p. 245–80.Google Scholar
  8. 8.
    Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology. 1988;8(5):1151–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Shoaf SE, Bramer SL, Bricmont P, Zimmer CA. Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, furosemide or hydrochlorothiazide. J Cardiovasc Phamacol. 2007;50(2):213–22.CrossRefGoogle Scholar
  10. 10.
    Inuyama Symposium Kirokukannkoukai, editors. Proceedings of the 12th Inuyama Symposium: hepatitis A and fulminant hepatitis (in Japanese). Tokyo: Chugai Igakusha; 1982. p. 124.Google Scholar
  11. 11.
    Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, Kambayashi J, Zampino M, et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation. 2003;107(21):2690–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Gheorghiade M, Konstam MA, Burnet JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials. JAMA. 2007;297(12):1332–43.CrossRefPubMedGoogle Scholar
  13. 13.
    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.CrossRefPubMedGoogle Scholar
  14. 14.
    Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099–112.CrossRefPubMedGoogle Scholar
  15. 15.
    Lin SH, Hsu YJ, Chiu JS, Chu SJ, Davids MR, Halperin ML, et al. Osmotic demyelination syndrome: a potentially avoidable disaster. Q J Med. 2003;96:935–47.Google Scholar
  16. 16.
    Verbalis JG, Goldsmith SR, Greenberg A, Schrier RW, Sterns RH, et al. Hyponatremia treatment guidelines 2007: expert panel recommendations. Am J Med. 2007;120(11 Suppl 1):S1–21.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Kiwamu Okita
    • 1
    Email author
  • Isao Sakaida
    • 2
  • Mitsuru Okada
    • 3
  • Akira Kaneko
    • 4
  • Kazuaki Chayama
    • 5
  • Michio Kato
    • 6
  • Michio Sata
    • 7
  • Naomasa Yoshihara
    • 8
  • Noriyuki Ono
    • 9
  • Yoshikazu Murawaki
    • 10
  1. 1.Social Insurance Alliance Shimonoseki Kohsei HospitalShimonosekiJapan
  2. 2.Department of Gastroenterology and HepatologyYamaguchi University Graduate School of MedicineUbeJapan
  3. 3.Otsuka Pharmaceutical Co., Ltd.OsakaJapan
  4. 4.Department of Internal MedicineNTT West Osaka HospitalOsakaJapan
  5. 5.Division of Frontier Medical Science, Department of Molecular Science, Programs for Biomedical Research, Graduate School of Biomedical ScienceHiroshima UniversityHiroshimaJapan
  6. 6.Department of GastroenterologyNational Hospital Organization Minami Wakayama Medical CenterTanabeJapan
  7. 7.Division of Gastroenterology, Department of MedicineKurume University School of MedicineKurumeJapan
  8. 8.Department of Internal MedicineOsaka Rosai HospitalOsakaJapan
  9. 9.Department of General Medical CareChikugo City HospitalChikugoJapan
  10. 10.Department of Internal MedicineTottori University Medical School HospitalTottoriJapan

Personalised recommendations