Advertisement

Drugs

, Volume 75, Issue 15, pp 1797–1806 | Cite as

Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease

  • Hannah A. Blair
  • Gillian M. Keating
Adis Drug Evaluation

Abstract

Tolvaptan (Jinarc®) is a highly selective vasopressin V2 receptor antagonist indicated for use in patients with autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan is the first pharmaceutical agent to be approved in Europe for delaying the progression of ADPKD in adults with stage 1–3 chronic kidney disease at initiation of treatment. In the large phase III TEMPO 3:4 trial in adults with ADPKD, 3 years’ treatment with oral tolvaptan significantly reduced growth in total kidney volume and slowed renal function decline relative to placebo. Tolvaptan was also associated with a significantly lower rate of events for the composite secondary endpoint of time to investigator-assessed clinical progression relative to placebo, an effect that was largely attributable to reductions in the risk of worsening renal function and the risk of worsening kidney pain. Many of the most common adverse events in the tolvaptan group were related to its aquaretic mechanism of action (e.g. polyuria, nocturia, polydipsia and thirst). Tolvaptan was also associated with idiosyncratic elevations of liver enzymes which were reversible on discontinuation of the drug. Although the use of tolvaptan requires careful consideration and balancing of benefits and risks, current evidence suggests that tolvaptan is a promising new treatment option for patients with ADPKD.

Keywords

Autosomal Dominant Polycystic Kidney Disease Tolvaptan Urine Osmolality Free Water Clearance Total Kidney Volume 
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

During the peer review process, the manufacturer of tolvaptan was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Compliance with Ethical Standards

Funding

The preparation of this review was not supported by any external funding.

Conflicts of interest

Hannah Blair and Gillian Keating are salaried employees of Adis/Springer, are responsible for the article content and declare no relevant conflicts of interest.

References

  1. 1.
    Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287–301.CrossRefPubMedGoogle Scholar
  2. 2.
    Chapman AB, Devuyst O, Eckardt KU, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference. Kidney Int. 2015;88(1):17–27.CrossRefPubMedGoogle Scholar
  3. 3.
    McGovern AP, Jones S, van Vlymen J, et al. Identification of people with autosomal dominant polycystic kidney disease using routine data: a cross sectional study. BMC Nephrol. 2014;15:182.PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Neumann HP, Jilg C, Bacher J, et al. Epidemiology of autosomal-dominant polycystic kidney disease: an in-depth clinical study for south-western Germany. Nephrol Dial Transplant. 2013;28(6):1472–87.CrossRefPubMedGoogle Scholar
  5. 5.
    Ars E, Bernis C, Fraga G, et al. Spanish guidelines for the management of autosomal dominant polycystic kidney disease. Nephrol Dial Transplant. 2014;29(Suppl 4):iv95–105.CrossRefPubMedGoogle Scholar
  6. 6.
    Cornec-Le Gall E, Audrezet MP, Chen JM, et al. Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol. 2013;24(6):1006–13.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Wuthrich RP, Mei C. Pharmacological management of polycystic kidney disease. Expert Opin Pharmacother. 2014;15(8):1085–95.CrossRefPubMedGoogle Scholar
  8. 8.
    European Medicines Agency. Tolvaptan (Samsca): summary of product characteristics. http://www.ema.europa.eu. Accessed 18 Sep 2015.
  9. 9.
    Reif GA, Yamaguchi T, Nivens E, et al. Tolvaptan inhibits ERK-dependent cell proliferation, Cl(−) secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol. 2011;301(5):F1005–13.PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Meijer E, Gansevoort RT, de Jong PE, et al. Therapeutic potential of vasopressin V2 receptor antagonist in a mouse model for autosomal dominant polycystic kidney disease: optimal timing and dosing of the drug. Nephrol Dial Transplant. 2011;26(8):2445–53.CrossRefPubMedGoogle Scholar
  11. 11.
    European Medicines Agency. Tolvaptan (Jinarc): summary of product characteristics. 2015. http://www.ema.europa.eu. Accessed 18 Sep 2015.
  12. 12.
    Aihara M, Fujiki H, Mizuguchi H, et al. Tolvaptan delays the onset of end-stage renal disease in a polycystic kidney disease model by suppressing increases in kidney volume and renal injury. J Pharmacol Exp Ther. 2014;349(2):258–67.CrossRefPubMedGoogle Scholar
  13. 13.
    Shoaf SE, Wang Z, Bricmont P, et al. Pharmacokinetics, pharmacodynamics, and safety of tolvaptan, a nonpeptide AVP antagonist, during ascending single-dose studies in healthy subjects. J Clin Pharmacol. 2007;47(12):1498–507.CrossRefPubMedGoogle Scholar
  14. 14.
    European Medicines Agency. Jinarc assessment report. 2015. http://www.ema.europa.eu. Accessed 18 Sep 2015.
  15. 15.
    Torres VE, Meijer E, Bae KT, et al. Rationale and design of the TEMPO (tolvaptan efficacy and safety in management of autosomal dominant polycystic kidney disease and its outcomes) 3–4 study. Am J Kidney Dis. 2011;57(5):692–9.PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Higashihara E, Torres VE, Chapman AB, et al. Tolvaptan in autosomal dominant polycystic kidney disease: three years’ experience. Clin J Am Soc Nephrol. 2011;6(10):2499–507.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Irazabal MV, Torres VE, Hogan MC, et al. Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease. Kidney Int. 2011;80(3):295–301.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Boertien WE, Meijer E, de Jong PE, et al. Short-term effects of tolvaptan in individuals with autosomal dominant polycystic kidney disease at various levels of kidney function. Am J Kidney Dis. 2015;65(6):833–41.CrossRefPubMedGoogle Scholar
  19. 19.
    Boertien WE, Meijer E, de Jong PE, et al. Short-term renal hemodynamic effects of tolvaptan in subjects with autosomal dominant polycystic kidney disease at various stages of chronic kidney disease. Kidney Int. 2013;84(6):1278–86.CrossRefPubMedGoogle Scholar
  20. 20.
    Shoaf SE, Bramer SL, Bricmont P, et al. Pharmacokinetic and pharmacodynamic interaction between tolvaptan, a non-peptide AVP antagonist, and furosemide or hydrochlorothiazide. J Cardiovasc Pharmacol. 2007;50(2):213–22.CrossRefPubMedGoogle Scholar
  21. 21.
    Shoaf SE, Bricmont P, Mallikaarjun S. Pharmacokinetics and pharmacodynamics of oral tolvaptan in patients with varying degrees of renal function. Kidney Int. 2014;85(4):953–61.PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Shoaf SE, Kim SR, Bricmont P, et al. 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.CrossRefPubMedGoogle Scholar
  23. 23.
    Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407–18.PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Torres VE, Devuyst O, Chapman AB, et al. Effect of tolvaptan in ADPKD by CKD stage: results from the TEMPO 3:4 trial [abstract plus poster]. In: World Congress of Nephrology; 2015.Google Scholar
  25. 25.
    Muto S, Kawano H, Higashihara E, et al. The effect of tolvaptan on autosomal dominant polycystic kidney disease patients: a subgroup analysis of the Japanese patient subset from TEMPO 3:4 trial. Clin Exp Nephrol. 2015. doi: 10.1007/s10157-015-1086-2.Google Scholar
  26. 26.
    Devuyst O, Chapman AB, Boklage S, et al. Tolerability of aquaretic-related symptoms: results from the TEMPO 3:4 trial [abstract plus poster]. In: World Congress of Nephrology; 2015.Google Scholar
  27. 27.
    Watkins PB, Lewis JH, Kaplowitz N, et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 2015. doi: 10.1007/s40264-015-0327-3.PubMedGoogle Scholar
  28. 28.
    Nagao S, Nishii K, Katsuyama M, et al. Increased water intake decreases progression of polycystic kidney disease in the PCK rat. J Am Soc Nephrol. 2006;17(8):2220–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Wang X, Wu Y, Ward CJ, et al. Vasopressin directly regulates cyst growth in polycystic kidney disease. J Am Soc Nephrol. 2008;19(1):102–8.PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Torres VE, Wang X, Qian Q, et al. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004;10(4):363–4.CrossRefPubMedGoogle Scholar
  31. 31.
    Ong AC, Devuyst O, Knebelmann B, et al. Autosomal dominant polycystic kidney disease: the changing face of clinical management. Lancet. 2015;385(9981):1993–2002.CrossRefPubMedGoogle Scholar
  32. 32.
    Alam A, Dahl NK, Lipschutz JH, et al. Total kidney volume in autosomal dominant polycystic kidney disease: a biomarker of disease progression and therapeutic efficacy. Am J Kidney Dis. 2015. doi: 10.1053/j.ajkd.2015.01.030.PubMedGoogle Scholar
  33. 33.
    Bhutani H, Smith V, Rahbari-Oskoui F, et al. A comparison of ultrasound and magnetic resonance imaging shows that kidney length predicts chronic kidney disease in autosomal dominant polycystic kidney disease. Kidney Int. 2015;88(1):146–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Otsuka Pharmaceutical Development and Commercialization. Open-label tolvaptan study in subjects with ADPKD (TEMPO 4/4). 2014. http://www.clinicaltrials.gov/ct2/show/NCT01214421. Accessed 18 Sep 2015.
  35. 35.
    Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan-treatment of ADPKD confers persistent EGFR improvement: results from the TEMPO 4:4 extension trial [abstract no. SO016]. In: 51st European Renal Association–European Dialysis and Transplant Association (ERA–EDTA) Congress; 2014.Google Scholar
  36. 36.
    Spital A. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013;368(13):1257.CrossRefPubMedGoogle Scholar
  37. 37.
    Black P, Sutton R. Commentary on: Tolvaptan in patients with autosomal-dominant polycystic kidney disease. Urology. 2013;81(4):705–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Torres VE, Gansevoort RT, Czerwiec FS. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013;368(13):1259.PubMedGoogle Scholar
  39. 39.
    National Institute for Health and Care Excellence. Final appraisal determination document—tolvaptan for treating autosomal dominant polycystic kidney disease. 2015. http://www.nice.org.uk. Accessed 18 Sep 2015.
  40. 40.
    Robinson P, McEwan P, Ong ACM, et al. Assessing the long term outcomes of autosomal dominant polycystic kidney disease (ADPKD) using the ADPKD outcomes model: a UK case study [abstract no. FP064 plus poster]. In: 52nd European Renal Association–European Dialysis and Transplant Association (ERA–EDTA) Congress. 2015.Google Scholar
  41. 41.
    O’Reilly K, McEwan P, Bennett Wilton H, et al. Exploring the impact of tolvaptan on the long term rate of renal function decline using the ADPKD outcomes model [abstract no. FP055 plus poster]. In: 52nd European Renal Association–European Dialysis and Transplant Association (ERA–EDTA) Congress. 2015.Google Scholar
  42. 42.
    Blanchette CM, Matter S, Chawla A, et al. Burden of autosomal dominant polycystic kidney disease: systemic literature review. Am J Pharm Benefits. 2015;7(2):e27–36.Google Scholar
  43. 43.
    Otsuka Pharmaceutical Development and Commercialization. Efficacy and safety of tolvaptan in subjects with chronic kidney disease between late stage 2 to early stage 4 due to autosomal dominant polycystic kidney disease. 2014. http://www.clinicaltrials.gov/ct2/show/NCT02160145. Accessed 18 Sep 2015.
  44. 44.
    Otsuka Pharmaceutical Development and Commercialization. Open-label trial to evaluate the long term safety of titrated immediate-release tolvaptan in subjects with autosomal dominant polycystic kidney disease. 2014. http://www.clinicaltrials.gov/ct2/show/NCT02251275. Accessed 18 Sep 2015.

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

Personalised recommendations