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Drugs

, Volume 79, Issue 3, pp 303–313 | Cite as

Tolvaptan: A Review in Autosomal Dominant Polycystic Kidney Disease

  • Hannah A. BlairEmail author
Adis Drug Evaluation

Abstract

Tolvaptan [Jynarque® (USA); Jinarc® (EU, Canada); Samsca® (Japan)] is a highly selective vasopressin V2 receptor antagonist approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). In the phase III TEMPO 3:4 trial, 3 years’ treatment with tolvaptan slowed the increase in total kidney volume (TKV) and the decline in renal function relative to placebo. The composite secondary endpoint of time to investigator-assessed clinical progression also favoured tolvaptan over placebo. Although tolvaptan did not demonstrate a sustained disease-modifying effect on TKV over the longer term in the TEMPO 4:4 extension trial, the effect of tolvaptan in slowing renal function decline was maintained for a further 2 years. The phase III REPRISE trial confirmed the efficacy of tolvaptan in patients with later-stage ADPKD. Most of the adverse events commonly observed with tolvaptan (e.g. polyuria, nocturia, polydipsia, thirst) are consistent with its pharmacological activity. In the TEMPO trials, tolvaptan was also associated with idiosyncratic hepatotoxicity which was reversible on discontinuation of the drug. Although the use of tolvaptan requires careful consideration and balancing of benefits and risks, it provides a valuable treatment option to slow the progression of ADPKD in patients at risk of or with evidence of rapidly progressing disease.

Notes

Acknowledgements

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.

Conflict of interest

Hannah Blair is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

References

  1. 1.
    EAF co-chairs, Harris T, Sandford R, et al. European ADPKD forum multidisciplinary position statement on autosomal dominant polycystic kidney disease care: European ADPKD forum and multispecialist roundtable participants. Nephrol Dial Transplant. 2018;33(4):563–73.CrossRefGoogle Scholar
  2. 2.
    Simms RJ. Autosomal dominant polycystic kidney disease. BMJ. 2016;352:i679.CrossRefGoogle Scholar
  3. 3.
    Chang MY, Ong AC. Mechanism-based therapeutics for autosomal dominant polycystic kidney disease: recent progress and future prospects. Nephron Clin Pract. 2012;120(1):c25–34.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefGoogle Scholar
  6. 6.
    Blair HA, Keating GM. Tolvaptan: a review in autosomal dominant polycystic kidney disease. Drugs. 2015;75(15):1797–806.CrossRefGoogle Scholar
  7. 7.
    European Medicines Agency. Jinarc (tolvaptan): EU summary of product characteristics. 2018. http://www.ema.europa.eu. Accessed 10 Jan 2019.
  8. 8.
    US FDA. JYNARQUE (tolvaptan) tablets for oral use: US prescribing information. 2018. http://www.fda.gov. Accessed 10 Jan 2019.
  9. 9.
    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.CrossRefGoogle Scholar
  10. 10.
    Torres VE, Chapman AB, Devuyst O, et al. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 trial. Nephrol Dial Transplant. 2018;33(3):477–89.CrossRefGoogle Scholar
  11. 11.
    Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in later-stage autosomal dominant polycystic kidney disease. N Engl J Med. 2017;377(20):1930–42.CrossRefGoogle Scholar
  12. 12.
    Oguro M, Kogure Y, Hoshino J, et al. Tolvaptan in Japanese patients with later-stage autosomal dominant polycystic kidney disease. J Nephrol. 2018;31(6):961–6.CrossRefGoogle Scholar
  13. 13.
    Torres VE, Higashihara E, Devuyst O, et al. Effect of tolvaptan in autosomal dominant polycystic kidney disease by CKD stage: results from the TEMPO 3:4 trial. Clin J Am Soc Nephrol. 2016;11(5):803–11.CrossRefGoogle Scholar
  14. 14.
    Irazabal MV, Blais JD, Perrone RD, et al. Prognostic enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the TEMPO 3:4 clinical trial. Kidney Int Rep. 2016;1(4):213–20.CrossRefGoogle Scholar
  15. 15.
    Gansevoort RT, Meijer E, Chapman AB, et al. Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 trial. Nephrol Dial Transplant. 2016;31(11):1887–94.CrossRefGoogle Scholar
  16. 16.
    Casteleijn NF, Blais JD, Chapman AB, et al. Tolvaptan and kidney pain in patients with autosomal dominant polycystic kidney disease: secondary analysis from a randomized controlled trial. Am J Kidney Dis. 2017;69(2):210–9.CrossRefGoogle Scholar
  17. 17.
    Chapman A, Devusyt O, Gansevoort R, et al. Potential impact of tolvaptan on blood pressure in the TEMPO 3:4 patient population [abstract no. FP047]. Nephrol Dial Transplant. 2018;33(Suppl 1):i63.Google Scholar
  18. 18.
    Grantham JJ, Chapman AB, Blais J, et al. Tolvaptan suppresses monocyte chemotactic protein-1 excretion in autosomal-dominant polycystic kidney disease. Nephrol Dial Transplant. 2016;32(6):969–75.Google Scholar
  19. 19.
    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 and Exp Nephrol. 2015;19(5):867–77.CrossRefGoogle Scholar
  20. 20.
    Yamada K, Muramoto H, Araki H, et al. Effectiveness and safety of tolvaptan in autosomal dominant polycystic kidney disease patients with CKD stage G4: a retrospective multicenter study in Japan [abstract no. FP052]. Nephrol Dial Transplant. 2018;33(Suppl 1):i65.Google Scholar
  21. 21.
    Russmann S, Grimes E, Neidrig D, et al. Safety and efficacy of tolvaptan in the SUISSE ADPKD cohort [abstract no. 1386]. Drug Saf. 2018;41(11):1229.Google Scholar
  22. 22.
    Hattanda F, Nishio S, Takeda S, et al. Efficacy of tolvaptan on autosomal dominant polycystic kidney disease (ADPKD) patients in late stage CKD [abstract no. SP027]. Nephrol Dial Transplant. 2018;33(Suppl 1):i355.Google Scholar
  23. 23.
    Kai H, Tsunoda R, Kawamura T, et al. A prospective study of the efficacy and adverse effects of tolvaptan for autosomal dominant polycystic kidney disease (ADPKD) [abstract no. FP061]. Nephrol Dial Transplant. 2018;33(Suppl. 1):i68.Google Scholar
  24. 24.
    Cote G, Asselin-Thompstone L, Rene De Cotret P, et al. The impact of tolvaptan on glomerular filtration rate in patients with autostomal dominant polycystic kidney disease [abstract no. SA-PO476]. J Am Soc Nephrol. 2018;29(Suppl):859.Google Scholar
  25. 25.
    Honda K, Matsuura R, Ishimoto Y, et al. Association between initial dose of tolvaptan and reduction of total kidney volume in autostomal dominant polycystic kidney disease [abstract no. SA-PO477]. J Am Soc Nephrol. 2018;29(Suppl):859.Google Scholar
  26. 26.
    Kogure Y, Takayanagi K, Sato M, et al. Clinical features expecting high efficacy of tolvaptan in ADPKD patients [abstract no. SA-PO478]. J Am Soc Nephrol. 2018;29(Suppl):859.Google Scholar
  27. 27.
    Mueller R-U, Todorova P, Suarez V, et al. AD(H)PKD—a prospective cohort study on the use of tolvaptan in ADPKD [abstract no. SA-PO473]. J Am Soc Nephrol. 2018;29(Suppl):858.Google Scholar
  28. 28.
    Muto S, Okada T, Yasuda M, et al. Long-term safety profile of tolvaptan in autosomal dominant polycystic kidney disease patients: TEMPO extension Japan trial. Drug Healthc Patient Saf. 2017;9:93–104.CrossRefGoogle Scholar
  29. 29.
    Devuyst O, Chapman AB, Shoaf SE, et al. Tolerability of aquaretic-related symptoms following tolvaptan for autosomal dominant polycystic kidney disease: results from TEMPO 3:4. Kidney Int Rep. 2017;2(6):1132–40.CrossRefGoogle Scholar
  30. 30.
    McFarlane P, Bichet DG, Bergeron L, et al. Canadian real-life assessment of tolvaptan in autosomal dominant polycystic kidney disease (ADPKD): C-MAJOR study and hepatic safety monitoring program [abstract no. SA-PO480]. J Am Soc Nephrol. 2018;29(Suppl):860.Google Scholar
  31. 31.
    Sommerer C, Zeier M. Clinical manifestation and management of ADPKD in western countries. Kidney Dis. 2016;2(3):120–7.CrossRefGoogle Scholar
  32. 32.
    Soroka S, Alam A, Bevilacqua M, et al. Updated Canadian expert consensus on assessing risk of disease progression and pharmacological management of autosomal dominant polycystic kidney disease. Can J Kidney Health Dis. 2018.  https://doi.org/10.1177/2054358118801589.
  33. 33.
    Chebib FT, Perrone RD, Chapman AB, et al. A practical guide for treatment of rapidly progressive ADPKD with tolvaptan. J Am Soc Nephrol. 2018;29:1–13.CrossRefGoogle Scholar
  34. 34.
    Gansevoort RT, Arici M, Benzing T, et al. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA working groups on inherited kidney disorders and European renal best practice. Nephrol Dial Transplant. 2016;31(3):337–48.CrossRefGoogle Scholar
  35. 35.
    National Institute for Health and Care Excellence (NICE). Tolvaptan for treating autosomal dominant polycystic kidney disease. 2015. http://www.nice.org.uk. Accessed 10 Jan 2019.
  36. 36.
    Mustafa RA, Yu ASL. Burden of proof for tolvaptan in ADPKD: did REPRISE provide the answer? Clin J Am Soc Nephrol. 2018;13(7):1107–9.Google Scholar
  37. 37.
    Wyatt CM, Le Meur Y. REPRISE: tolvaptan in advanced polycystic kidney disease. Kidney Int. 2018;93(2):292–5.CrossRefGoogle Scholar
  38. 38.
    van Gastel MDA, Torres VE. Polycystic kidney disease and the vasopressin pathway. Ann Nutr Metab. 2017;70(Suppl 1):43–50.CrossRefGoogle Scholar
  39. 39.
    Wong ATY, Mannix C, Grantham JJ, et al. Randomised controlled trial to determine the efficacy and safety of prescribed water intake to prevent kidney failure due to autosomal dominant polycystic kidney disease (PREVENT-ADPKD). BMJ open. 2018;8(1):e018794.Google Scholar
  40. 40.
    UKidney. Water vs tolvaptan in reducing ADPKD progression. http://ukidney.com. Accessed 10 Jan 2019.
  41. 41.
    Gross P, Schirutschke H, Paliege A. Con: tolvaptan for autosomal dominant polycystic kidney disease-do we know all the answers? Nephrol Dial Transplant. 2018;34(1):35–7.CrossRefGoogle Scholar
  42. 42.
    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;38(11):1103–13.CrossRefGoogle Scholar
  43. 43.
    Woodhead JL, Brock WJ, Roth SE, et al. Application of a mechanistic model to evaluate putative mechanisms of tolvaptan drug-induced liver injury and identify patient susceptibility factors. Toxicol Sci. 2017;155(1):61–74.CrossRefGoogle Scholar
  44. 44.
    European Medicines Agency. Jinarc assessment report. 2015. http://www.ema.europa.eu. Accessed 10 Jan 2019.
  45. 45.
    US National Institutes of Health. 2018. http://www.clinicaltrials.gov. Accessed 10 Jan 2019.
  46. 46.
    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
  47. 47.
    Bennett H, McEwan P, Robinson P, et al. Validation of the ADPKD outcomes model to a Spanish setting and an evaluation of the impact of treatment on the burden of ESRD [abstract no. PUK23 plus poster]. Value Health. 2017;20(5):A309–A10.Google Scholar
  48. 48.
    Shephard C, Delavelle C, Riemer J, et al. Impact of tolvaptan on costs associated with renal pain and chronic kidney disease among patients with autosomal dominant polycystic kidney disease [abstract no. 274]. Am J Kidney Dis. 2018;71(4):584.Google Scholar
  49. 49.
    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.CrossRefGoogle Scholar
  50. 50.
    Lee Y, Blount KL, Dai F, et al. Semaphorin 7A in circulating regulatory T cells is increased in autosomal-dominant polycystic kidney disease and decreases with tolvaptan treatment. Clin Exp Nephrol. 2018;22(4):906–16.CrossRefGoogle Scholar
  51. 51.
    Fujiki T, Ando F, Isobe K, et al. Tolvaptan activates Nrf2/HO-1 pathway through PERK phosphorylation [abstract no. SA-PO847]. J Am Soc Nephrol. 2018;29(Suppl):957.Google Scholar
  52. 52.
    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.CrossRefGoogle Scholar
  53. 53.
    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.CrossRefGoogle Scholar
  54. 54.
    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.CrossRefGoogle Scholar
  55. 55.
    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.CrossRefGoogle Scholar
  56. 56.
    Harskamp LR, Gansevoort RT, Boertien WE, et al. Urinary EGF receptor ligand excretion in patients with autosomal dominant polycystic kidney disease and response to tolvaptan. Clin J Am Soc Nephrol. 2015;10(10):1749–56.CrossRefGoogle Scholar
  57. 57.
    Minami S, Hamano T, Iwatani H, et al. Tolvaptan promotes urinary excretion of sodium and urea: a retrospective cohort study. Clin Exp Nephrol. 2018;22(3):550–61.CrossRefGoogle Scholar
  58. 58.
    Al Therwani S, Malmberg MES, Rosenbaek JB, et al. Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study. BMC Nephrol. 2017;18(1):268.CrossRefGoogle Scholar
  59. 59.
    Kawano H, Muto S, Ohmoto Y, et al. Exploring urinary biomarkers in autosomal dominant polycystic kidney disease. Clin Exp Nephrol. 2015;19(5):968–73.CrossRefGoogle Scholar
  60. 60.
    Malmberg M, Sonderbaek R, Mose F, et al. Effect of tolvaptan on renal plasma flow and glomerular filtration in polycystic kidney disease [abstract no. SP110]. Nephrol Dial Transplant. 2018;33(Suppl 1):i381.Google Scholar
  61. 61.
    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.CrossRefGoogle Scholar
  62. 62.
    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.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.SpringerAucklandNew Zealand

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