Advances in Therapy

, Volume 33, Issue 7, pp 1140–1157 | Cite as

Characteristics of the Novel Potassium-Competitive Acid Blocker Vonoprazan Fumarate (TAK-438)

  • Kazuyoshi OtakeEmail author
  • Yuuichi Sakurai
  • Haruyuki Nishida
  • Hideo Fukui
  • Yoshihiko Tagawa
  • Hitomi Yamasaki
  • Masatoshi Karashima
  • Keiichi Otsuka
  • Nobuhiro Inatomi


Proton pump inhibitors (PPIs) are widely prescribed as first-line therapy for the treatment of acid-related diseases, such as peptic ulcers and gastro-esophageal reflux disease, and for the eradication of Helicobacter pylori. However, the therapeutic efficacy of conventional PPIs is considered limited because: (1) they are unstable under acidic conditions and require an enteric-coated formulation in clinical use; (2) they show high interindividual variability in pharmacokinetics due to genetic polymorphisms of cytochrome P450 (CYP) 2C19 metabolism; (3) they have a relatively slow onset of pharmacological action and may require several doses to achieve optimal acid suppression and symptom relief; and (4) they often do not provide stable suppression of gastric acid secretion over 24 h. Vonoprazan fumarate (TAK-438, hereinafter referred to as “vonoprazan”) is a new potassium-competitive acid blocker (P-CAB) developed to resolve the above limitations of conventional PPIs. Various physicochemical data have shown that vonoprazan has a high solubility and stability over a broad pH range in aqueous conditions. In addition, vonoprazan has a more potent and longer-lasting acid suppression effect than the conventional PPI, lansoprazole. Preclinical pharmacokinetic studies have shown that vonoprazan is accumulated and retained in the stomach for more than 24 h, even after it is eliminated from the plasma. From these findings, we propose that vonoprazan, which possesses a novel mode of action, can improve on the outcomes seen with conventional PPI-based treatments for acid-related diseases.


This review project, including the publication of this article, was funded by Takeda Pharmaceutical Company Limited.


Acid-related diseases Gastroenterology Helicobacter pylori eradication Lansoprazole Potassium-competitive acid blockers PPI Proton pump inhibitor Reflux esophagitis TAK-438 Vonoprazan 



Sponsorship and article processing charges for this study were funded by Takeda Pharmaceutical Company Limited.

We express our thanks to Mr. Masayuki Aboshi and Mr. Shigeki Okita of the Medical Science Liaison Group, Medical Affairs Department, Japan Research Center, Takeda Pharmaceutical Company Limited, and Mr. Francois Jones of Quintiles Transnational Japan Co., Ltd. for their support in drafting this article. We also thank the Medical Science Liaison Group, Medical Affairs Department, Japan Research Center, Takeda Pharmaceutical Company Limited for providing scientific advice. Dr. Keisuke Ishida of SunFlare Co., Ltd. provided medical writing support, which was funded by Takeda Pharmaceutical Company Limited. Mr. Yoshitaka Sato of Saikou, provided medical illustration service, which was funded by Takeda Pharmaceutical Company Limited.

This article was originally published in Japanese in the journal Progress in Medicine. Permission to translate and republish the article in English was granted by the publisher of Progress in Medicine. Kazuyoshi Otake, Yuichi Sakurai, Haruyuki Nishida, Hideo Fukui, Yoshihiko Tagawa, Hitomi Yamasaki, Masatoshi Karashima, Keiichi Otsuka, Nobuhiro Inatomi. Vonoprazan Fumarate (TAK-438). A New Potassium-Competitive Acid Blocker (P-CAB) with a Novel Mode of Action—physicochemical Properties, Non-Clinical Data, and a Proposed Mode of Action. Progress in Medicine 2014:34(12):2183–2194. Translation of the article from Japanese to English was funded by Takeda Pharmaceuticals USA, Inc. and performed by a native Japanese-speaking translator specialized in the life sciences. The translation was conducted according to rigid ISO 9001:2008 and EN 15038:2006 certified quality assurance processes. This article is a translation of the original Japanese article to English with updates.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.


Kazuyoshi Otake, Yuuichi Sakurai, Haruyuki Nishida, Hideo Fukui, Yoshihiko Tagawa, Hitomi Yamasaki, Masatoshi Karashima, Keiichi Otsuka and Nobuhiro Inatomi are employees of Takeda Pharmaceutical Company Limited, and there are no other applicable matters regarding conflicts of interest.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.


  1. 1.
    Huang JQ, Hunt RH. pH, healing rate and symptomatic relief in acid-related diseases. Yale J Biol Med. 1996;69:159–74.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Hirschowitz BI, Keeling D, Lewin M, et al. Pharmacological aspects of acid secretion. Dig Dis Sci. 1995;40(2 Suppl):3S–23S.CrossRefPubMedGoogle Scholar
  3. 3.
    Urushidani T, Nagao T. Calyculin A, a phosphoprotein phosphatase inhibitor, stimulates acid secretion in isolated gastric glands. Am J Physiol. 1996;270(1 Pt 1):G103–12.PubMedGoogle Scholar
  4. 4.
    Forte JG, Ganser A, Beesley R, Forte TM. Unique enzymes of purified microsomes from pig fundic mucosa. K+-stimulated adenosine triphosphatase and K+-stimulated pNPPase. Gastroenterology. 1975;69:175–89.PubMedGoogle Scholar
  5. 5.
    Chow DC, Forte JG. Functional significance of the beta-subunit for heterodimeric P-type ATPases. J Exp Biol. 1995;198:1–17.PubMedGoogle Scholar
  6. 6.
    Rabon E, Cuppoletti J, Malinowska D, et al. Proton secretion by the gastric parietal cell. J Exp Biol. 1983;106:119–33.PubMedGoogle Scholar
  7. 7.
    Herrmann M, Selige J, Raffael S, Sachs G, Brambilla A, Klein T. Systematic expression profiling of the gastric H+/K+ ATPase in human tissue. Scand J Gastroenterol. 2007;42:1275–88.CrossRefPubMedGoogle Scholar
  8. 8.
    Kraut JA, Helander KG, Helander HF, Iroezi ND, Marcus EA, Sachs G. Detection and localization of H+-K+-ATPase isoforms in human kidney. Am J Physiol Renal Physiol. 2001;281(4):F763–8.PubMedGoogle Scholar
  9. 9.
    Forte JG, Hanzel DK, Okamoto C, Chow D, Urushidani T. Membrane and protein recycling associated with gastric HCl secretion. J Intern Med Suppl. 1990;732:17–26.CrossRefPubMedGoogle Scholar
  10. 10.
    Howden CW, Burget DW, Hunt RH. Appropriate acid suppression for optimal healing of duodenal ulcer and gastro-oesophageal reflux disease. Scand J Gastroenterol Suppl. 1994;201:79–82.CrossRefPubMedGoogle Scholar
  11. 11.
    Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH. Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion. 1992;51(Suppl 1):59–67.PubMedGoogle Scholar
  12. 12.
    Hunt RH. Importance of pH control in the management of GERD. Arch Intern Med. 1999;159:649–57.CrossRefPubMedGoogle Scholar
  13. 13.
    Mössner J, Caca K. Developments in the inhibition of gastric acid secretion. Eur J Clin Invest. 2005;35:469–75.CrossRefPubMedGoogle Scholar
  14. 14.
    Sachs G, Meyer-Rosberg K, Scott DR, Melchers K. Acid, protons and Helicobacter pylori. Yale J Biol Med. 1996;69:301–16.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Asaka M, Kato M, Takahashi S, et al. Guidelines for the management of H. pylori infections: 2009 revised edition. Helicobacter. 2010;15:1–20.CrossRefPubMedGoogle Scholar
  16. 16.
    Yuan Y, Wang CC, Yuan YH, et al. The proportion of patients who are free of reflux symptoms during the initial days of treatment with proton pump inhibitors (PPIs) in GERD trials: a meta-analysis. Gastroenterology. 2008;134(Suppl 1):A174.Google Scholar
  17. 17.
    Hunt RH, Scarpignato C. Potassium-competitive acid blockers (P-CABs): are they finally ready for prime time in acid-related disease? Clin Trans Gastroenterol. 2015;6:e119. doi: 10.1038/ctg.2015.39.CrossRefGoogle Scholar
  18. 18.
    Scarpignato C, Hunt RH. Proton pump inhibitors: the beginning of the end or the end of the beginning? Curr Opin Pharmacol. 2008;8(6):677–84.CrossRefPubMedGoogle Scholar
  19. 19.
    Tytgat GN. Are there unmet needs in acid suppression? Best Pract Res Clin Gastroenterol. 2004;18(Suppl):67–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Fass R, Shapiro M, Dekel R, Sewell J. Systematic review: proton-pump inhibitor failure in gastro-oesophageal reflux disease - where next? Aliment Pharmacol Ther. 2005;22(2):79–94.CrossRefPubMedGoogle Scholar
  21. 21.
    Japanese Society for Gastroenterology. Guidelines for the management of GERD (2009).
  22. 22.
    Mégraud F. H pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut. 2004;53:1374–84.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut. 2010;59:1143–53.CrossRefPubMedGoogle Scholar
  24. 24.
    Ashida K. Notes on features and uses of medications used for PPI-resistant GERD, drugs under development and future prospects. Jpn J Med Pharm Sci. 2014;71:591–6.Google Scholar
  25. 25.
    Stewart B, Wallmark B, Sachs G. The interaction of H+ and K+ with the partial reactions of gastric (H++K+)-ATPase. J Biol Chem. 1981;256:2682–90.PubMedGoogle Scholar
  26. 26.
    Mendlein J, Sachs G. Interaction of a K+ -competitive inhibitor, a substituted imidazo[1,2a]pyridine, with the phospho- and dephosphoenzyme forms of H+, K+-ATPase. J Biol Chem. 1990;265:5030–6.PubMedGoogle Scholar
  27. 27.
    Parsons ME, Keeling DJ. Novel approaches to the pharmacological blockade of gastric acid secretion. Expert Opin Investig Drugs. 2005;14:411–21.CrossRefPubMedGoogle Scholar
  28. 28.
    Kahrilas PJ, Dent J, Lauritsen K, et al. A randomized, comparative study of three doses of AZD0865 and esomeprazole for healing of reflux esophagitis. Clin Gastroenterol Hepatol. 2007;5:1385–91.CrossRefPubMedGoogle Scholar
  29. 29.
    Berg AL, Böttcher G, Andersson K, et al. Early stellate cell activation and veno-occlusive-disease (VOD)-like hepatotoxicity in dogs treated with AR-H047108, an imidazopyridine proton pump inhibitor. Toxicol Pathol. 2008;36:727–37.CrossRefPubMedGoogle Scholar
  30. 30.
    Dent J, Kahrilas PJ, Hatlebakk J, et al. A randomized, comparative trial of a potassium-competitive acid blocker (AZD0865) and esomeprazole for the treatment of patients with nonerosive reflux disease. Am J Gastroenterol. 2008;103:20–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Kondo M, Kawamoto M, Hasuoka A, et al. High-throughput screening of potassium-competitive acid blockers. J Biomol Screen. 2012;17:177–82.CrossRefPubMedGoogle Scholar
  32. 32.
    Nishida H, Hasuoka A, Arikawa Y, et al. Discovery, synthesis, and biological evaluation of novel pyrrole derivatives as highly selective potassium-competitive acid blockers. Bioorg Med Chem. 2012;20:3925–38.CrossRefPubMedGoogle Scholar
  33. 33.
    Arikawa Y, Nishida H, Kurasawa O, et al. Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanaminefumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem. 2012;55:4446–56.CrossRefPubMedGoogle Scholar
  34. 34.
    Takeda Takecab (vonoprazan tablets). Japanese Common Technical Document. Available at: Accessed 20 Apr 2016.
  35. 35.
    Ashida K, Sakurai Y, Hori T, et al. Randomised clinical trial: vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the healing of erosive oesophagitis. Aliment Pharmacol Ther. 2016;43(2):240–51.CrossRefPubMedGoogle Scholar
  36. 36.
    Mizokami Y, Ashida K, Soen S, et al. TAK-438 versus lansoprazole 15 mg for secondary prevention of peptic ulcers associated with non-steroidal anti-inflammatory drug (NSAID) therapy: results of a phase 3 trial. Gastroenterology. 2014;146(5,Suppl 1):S-739.Google Scholar
  37. 37.
    Kawai T, Ashida K, Mizokami Y, et al. TAK-438 versus lansoprazole 15 mg for secondary prevention of peptic ulcers associated with low-dose aspirin therapy: results of a phase 3 trial. Gastroenterology. 2014;146(5,Suppl 1):S-739.Google Scholar
  38. 38.
    Murakami K, Sakurai Y, Shiino M, et al. Vonoprazan, a novel potassium-competitive acid blocker, as a component of first-line and second-line triple therapy for Helicobacter pylori eradication: a phase III, randomised, double-blind study. Gut. 2016. doi: 10.1136/gutjnl-2015-311304 (Epub ahead of print).
  39. 39.
    Hori Y, Matsukawa J, Takeuchi T, et al. A study comparing the antisecretory effect of TAK-438, a novel potassium-competitive acid blocker, with lansoprazole in animals. J Pharmacol Exp Ther. 2011;337:797–804.CrossRefPubMedGoogle Scholar
  40. 40.
    Hori Y, Imanishi A, Matsukawa J, et al. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther. 2010;335:231–8.CrossRefPubMedGoogle Scholar
  41. 41.
    Adachi K, Katsube T, Kawamura A, et al. CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Aliment Pharmacol Ther. 2000;14(10):1259–66.CrossRefPubMedGoogle Scholar
  42. 42.
    Furuta T, Ohashi K, Kosuge K, et al. CYP2C19 genotype status and effect of omeprazole on intragastric pH in humans. Clin Pharmacol Ther. 1999;65:552–61.CrossRefPubMedGoogle Scholar
  43. 43.
    Shirai N, Furuta T, Xiao F, et al. Comparison of lansoprazole and famotidine for gastric acid inhibition during the daytime and night-time in different CYP2C19 genotype groups. Aliment Pharmacol Ther. 2002;16(4):837–46.CrossRefPubMedGoogle Scholar
  44. 44.
    Yamada S, Onda M, Kato S, et al. Genetic differences in CYP2C19 single nucleotide polymorphisms among four Asian populations. J Gastroenterol. 2001;36:669–72.CrossRefPubMedGoogle Scholar
  45. 45.
    Furuta T, Shirai N, Kodaira M, et al. Pharmacogenomics-based tailored versus standard therapeutic regimen for eradication of H. pylori. Clin Pharmacol Ther. 2007;81:521–28.Google Scholar
  46. 46.
    Furuta T, Shirai N, Watanabe F, et al. Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole. Clin Pharmacol Ther. 2002;72:453–60.CrossRefPubMedGoogle Scholar
  47. 47.
    Kagami T, Sahara S, Ichikawa H, et al. Potent acid inhibition by vonoprazan in comparison with esomeprasole, with reference to CYP2C19 genotype. Aliment Pharmacol Ther. 2016;43(10):1048–59.CrossRefPubMedGoogle Scholar
  48. 48.
    Sakurai Y, Nishimura A, Kennedy G, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single rising TAK-438 (vonoprazan) doses in healthy male Japanese/non-Japanese subjects. Clin Transl Gastroenterol. 2015;25(6):e94.CrossRefGoogle Scholar
  49. 49.
    Jenkins H, Sakurai Y, Nishimura A, et al. Randomised clinical trial: safety, tolerability, pharmacokinetics and pharmacodynamics of repeated doses of TAK-438 (vonoprazan), a novel potassium-competitive acid blocker, in healthy male subjects. Aliment Pharmacol Ther. 2015;41(7):636–48.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Nagaya H, Satoh H, Kubo K, Maki Y. Possible mechanism for the inhibition of gastric (H++K+)-adenosine triphosphatase by the proton pump inhibitor AG-1749. J Pharmacol Exp Ther. 1989;248:799–805.PubMedGoogle Scholar
  51. 51.
    Fock KM, Ang TL, Bee LC, Lee EJ. Proton pump inhibitors: do differences in pharmacokinetics translate into differences in clinical outcomes? Clin Pharmacokinet. 2008;47:1–6.CrossRefPubMedGoogle Scholar
  52. 52.
    Gedda K, Scott D, Besancon M, Lorentzon P, Sachs G. Turnover of the gastric H+, K+-adenosine triphosphatase α subunit and its effect on inhibition of rat gastric acid secretion. Gastroenterology. 1995;109:1134–41.CrossRefPubMedGoogle Scholar
  53. 53.
    Sachs G. Improving on PPI-based therapy of GORD. Eur J Gastroenterol Hepatol. 2001;13(Suppl 1):S35–41.PubMedGoogle Scholar
  54. 54.
    Bytzer P, Blum AL. Personal view: rationale and proposed algorithms for symptom-based proton pump inhibitor therapy for gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2004;20(4):389–98.CrossRefPubMedGoogle Scholar
  55. 55.
    Sachs G, Shin JM, Howden CW. Review article: the clinical pharmacology of proton pump inhibitors. Aliment Pharmacol Ther. 2006;23(Suppl 2):2–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Tytgat GN. Shortcomings of the first-generation proton pump inhibitors. Eur J Gastroenterol Hepatol. 2001;13(Suppl 1):S29–33.PubMedGoogle Scholar
  57. 57.
    Shin JM, Inatomi N, Munson K, et al. Characterization of a novel potassium-competitive acid blocker of the gastric H, K-ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438). J Pharmacol Exp Ther. 2011;339:412–20.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Abe K, Tani K, Fujiyoshi Y. Conformational rearrangement of gastric H+, K+-ATPase induced by an acid suppressant. Nat Commun. 2011;2:155–61.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Matsukawa J, Hori Y, Nishida H, kajino M, Inatomi N. A comparative study on the modes of action of TAK-438, a novel potassium-competitive acid blocker, and lansoprazole in primary cultured rabbit gastric glands. Biochem Pharmacol. 2011;81:1145–51.Google Scholar
  60. 60.
    Takeda Takecab (vonoprazan tablets) package insert. Available at: Accessed 20 Apr 2016.
  61. 61.
    Hatlebakk JG, Katz PO, Camacho-Lobato L, Castell DO. Proton pump inhibitors: better acid suppression when taken before a meal than without a meal. Aliment Pharmacol Ther. 2000;14(10):1267–72.CrossRefPubMedGoogle Scholar
  62. 62.
    Wada F, Murase K, Isomoto H, et al. Polymorphism of CYP2C19 and gastric emptying in patients with proton pump inhibitor-resistant gastric ulcers. J Int Med Res. 2002;30:413–21.CrossRefPubMedGoogle Scholar
  63. 63.
    Klotz U. Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. Int J Clin Pharmacol Ther. 2006;44:297–302.CrossRefPubMedGoogle Scholar
  64. 64.
    Andersson K, Carlsson E. Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases. Pharmacol Ther. 2005;108:294–307.CrossRefPubMedGoogle Scholar
  65. 65.
    Zhou B, Huang Y, Li H, et al. Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int. 2016;27:339–47.CrossRefPubMedGoogle Scholar
  66. 66.
    Cunningham R, Dial S. Is over-use of proton pump inhibitors fuelling the current epidemic of Clostridium difficle-associated diarrhea? J Hosp Infect. 2008;70:1–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Healthcare 2016

Authors and Affiliations

  • Kazuyoshi Otake
    • 1
    Email author
  • Yuuichi Sakurai
    • 2
  • Haruyuki Nishida
    • 3
  • Hideo Fukui
    • 4
  • Yoshihiko Tagawa
    • 5
  • Hitomi Yamasaki
    • 5
  • Masatoshi Karashima
    • 6
  • Keiichi Otsuka
    • 7
  • Nobuhiro Inatomi
    • 8
  1. 1.Global Medical Affairs Japan DepartmentTakeda Pharmaceutical Co., Ltd.TokyoJapan
  2. 2.Clinical Science, Takeda Development Center JapanTakeda Pharmaceutical Co., Ltd.OsakaJapan
  3. 3.Medicinal Chemistry Research Laboratories, Pharmaceutical Research DivisionTakeda Pharmaceutical Co., Ltd.KanagawaJapan
  4. 4.Drug Safety Research Laboratories, Pharmaceutical Research DivisionTakeda Pharmaceutical Co., Ltd.KanagawaJapan
  5. 5.Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research DivisionTakeda Pharmaceutical Co., Ltd.KanagawaJapan
  6. 6.Analytical Development Laboratories, CMC CenterTakeda Pharmaceutical Co., Ltd.KanagawaJapan
  7. 7.Analytical Development Laboratories, CMC CenterTakeda Pharmaceutical Co., Ltd.OsakaJapan
  8. 8.Extra Value Generation Drug Discovery Unit, Pharmaceutical Research DivisionTakeda Pharmaceutical Co., Ltd.KanagawaJapan

Personalised recommendations