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Potassium-competitive acid blockers, a new therapeutic class, and their role in acid-related diseases: a narrative review

Gerson Domingues
Decio Chinzon
Joaquim Prado P. Moraes-Filho
Juliana Tosta Senra
Marcos Perrotti
Schlioma Zaterka

Internal Medicine – Gastroenterology Department, Medical School, State University of Rio de Janeiro, Rio de Janeiro, Brazil
Gastroenterology Department, Medical School, University of Sao Paulo, Sao Paulo, Brazil
Takeda Pharmaceuticals, Sao Paulo, Brazil
Gastroenterology Rev
Data publikacji online: 2022/08/15
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Acid-related diseases, also known as peptic-acid diseases, result from distinct but overlapping pathogenic mechanisms that involve acid effects on an oesophagogastric duodenal mucosa with diminished defence. Gastroesophageal reflux disease (GERD) – especially that leading to esophagitis, peptic ulcers, and ulcers caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA) – are some of the conditions that need to be highlighted [1, 2]. GERD represents the most frequently observed acid-related disease [1]. Globally, the mean prevalence in 2017 ranged from 4408 cases per 100,000 to 14,035 cases per 100,000 population, and countries from Latin America were among those with the highest values (> 11,000 cases per 100,000) [3]. In Brazil, estimates of the frequency of GERD or GERD symptoms such as heartburn ranged from 7.3% to 20.8% [4, 5]. In addition, 6.01 million years lived with disability were estimated considering only GERD in 2017, pointing to the relevant impact of acid-related diseases [3]. Regarding the occurrence of a peptic ulcer due to NSAID use, a study conducted in Brazil reported the association of the use of these medications and the presence of gastric lesions on endoscopy, with an increase in the risk of having gastric ulcer, gastric erosion with hematin, and gastric erosion of 2.17 (95% CI: 0.83–5.70), 2.91 (95% CI: 1.27–6.71), and 2.21 (95% CI: 1.50–3.27)-fold, respectively [6]. Treatment goals are related to symptoms relief, ulcer healing, and prevention of complications and recurrence [1]. Acid-related disease treatment is based on proton pump inhibitors (PPIs) worldwide [7–10]. In Brazil, PPIs have been the gold-standard treatment strategy for GERD management since the 1980s [11]. However, despite the efficiency of PPIs, several limitations lead to unmet medical needs in acid-related disease management, such as delay in the onset of the effect, low bioavailability, fast metabolism, drug interactions, variable sustainability of acid suppression, enteric-coated pharmaceutical form, and nocturnal acidity breakthrough [12]. In addition, it is estimated that about 6–15% and 40–50% of patients with non-erosive reflux disease and erosive oesophagitis, respectively, will fail to respond to treatment with PPIs [13]. This is especially true among patients with severe erosive disease (Los Angeles classifications C and D), in which failure rates are estimated at 20–30% [13]. The global failure of PPI therapy results in persistence of symptoms, occurrence of new symptoms, and relapse of healed oesophagitis during maintenance therapy. In this context, a new therapeutic class, potassium-competitive acid blockers (P-CABs), has emerged to promote a superior antisecretory effect addressing these unmet needs related to acid-related disease management [14]. Pharmaceutical companies have proposed several drugs from the P-CABs class; however, safety issues have led to discontinuation of most of them. Vonoprazan fumarate and revaprazan showed better safety profiles and were the first drugs of the P-CABs class to be approved by regulatory agencies [15, 16]. Vonoprazan is a new molecule recently approved by the Brazilian National Health Surveillance Agency (ANVISA, Agencia Nacional de Vigilancia Sanitaria), which could bring more answers for acid-related diseases’ unmet needs in the country [17].


This narrative review was conducted to provide an overview of the general concepts regarding P-CABs, focussing on vonoprazan fumarate.

Material and methods

A literature search was conducted through April–May 2021, using PubMed, LILACS (Literatura Latino-Americana e do Caribe em Ciencias da Saude), and the Scielo databases, using terms related to acid-related diseases and P-CABs. Non-structured searches for efficacy and safety information were performed using a combination of MeSH controlled vocabulary and text words such as “vonoprazan”, “1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine”, “TAK 438”, and “YH 1885”. Papers that described pivotal and novel insights about P-CABs and vonoprazan fumarate were selected. Additional studies were also found using the bibliographies of selected articles.

Historical evolution of treatment of acid-related diseases’

Lifestyle interventions were the first strategy to be proposed based on the assumption that obesity, smoking, alcohol consumption, body position, and food intake could prevent the retrograde flow of gastric contents. Later, acid inhibitors were developed to treat GERD by inhibiting acid secretion, considering that acid exposure could explain acid-related diseases. Antacids were initially proposed based on the association of the condition with an excessive amount of gastric acid; other medications include histamine H2-receptor antagonists (H2RAS), prokinetics, and PPIs [11]. The use of PPIs emerged from the observation of the gastric H+/K+-ATPase on the proton pump as the final step of the acid secretion pathway, turning into the preferred treatment option. However, unmet medical needs related to insufficient gastric acid suppression due to pharmacological limitations are still observed [18]. In the early 1980s, the first P-CAB was developed considering the rationale that this substance could inhibit H+,K+-ATPase in a reversible and K+-competitive manner, which turned into an almost complete gastric acid secretion inhibition since the first dose [15, 18]. The synthesis of a series of N-(5-aryl-1-arylsulfonyl-1H-pyrrole-3-yl) methyl-N-methylmethanamine derivatives resulted in the finding of a compound with potent H+,K+-ATPase inhibition in vitro, and it was selected to be a drug candidate [19]. This compound was an object of further studies, and it is known as vonoprazan fumarate [16]. Recently, ANVISA approved P-CABs vonoprazan, as shown in Figure 1, for GERD management and for the treatment of other acid-related diseases [17]; in Brazil there is no regulatory indication for H. pylori eradication, but vonoprazan-based triple therapy (vonoprazan, amoxicillin, and clarithromycin) or double therapy with 4 g of amoxicillin both for 7 days has shown an eradication rate of approximately 90% [20].

P-CABs: historical evolution

The class of P-CABs was first described in the 1980s. SCH28080, an imidazopyridine compound, was developed and showed inhibition of gastric acid secretion in humans and animals. In addition, the compound was shown to inhibit H+,K+-ATPase via competitive interaction with the K+ site of the enzyme. However, clinical studies were discontinued due to hepatic toxicity after prolonged administration. Then, a series of studies using SCH28080 derivatives was initiated [15, 21]. Compounds such as linazapran (imidazopyridine derivative), sorazapran (imidazonaphthyridine derivative), SPI-447 (imidazothienopyridine), SK&F96067 and SK&F97574 (quinolone derivative), CS-526 (pyrrolopyridazine derivative), revaprazan (pyrimidine derivative), and vonoprazan (pyrrole derivative) were developed [15]. Two P-CABs are available for use in clinical practice, and they are indicated to manage acid-related diseases. Revaprazan was the first P-CAB used, initially launched in South Korea to treat duodenal ulcer, gastric ulcer, and gastritis, and now also available in India. Vonoprazan was launched in Japan in 2015 to be used for the treatment of gastric ulcer, duodenal ulcer, erosive oesophagitis, and prevention of low-dose aspirin- or NSAID-induced ulcer recurrence [15, 21]. In 2019 it was approved in China for the management of gastric/duodenal ulcer and reflux oesophagitis [22].

P-CABs: mechanism of action

P-CABs are characterized as weak bases, and their protonated form can block the K+ exchange channel of H+, K+-ATPase in the proton pump. The pKa is an important marker: the lower the pKa value, the stronger the acid. The pKa of these drugs varies between 5.6 (SCH28080), 6.1 (linaprazan), and 9.3 (vonoprazan). Considering that vonoprazan has a high pKa (at 9.3), most of it is protonated easily and exerts its inhibitory action. Additionally, because the protonated forms are less prone to cross membranes than the non-ionic molecules, these protonated forms of P-CABs concentrate in the acid-secreting canaliculi of parietal cells where inhibit H+, K+-ATPase enzyme [21, 23]. One disadvantage of PPIs was the acidic parietal cell pH requirement to facilitate the conversion of the prodrug to its active form for the pharmacological effect. On the other hand, the K+ competitive acid blockers do not depend on acid activation but bind to the enzyme directly with a rapid onset action and better control of acid secretion [21, 23]. P-CABs block the K+ exchange channel of the proton pump, resulting in fast, competitive, reversible inhibition of acid secretion [23]. However, because they bind reversibly and not covalently, a constant plasma concentration of the drug has to be maintained for sustained effect. As a result, as shown in Figure 2, they may have a longer duration of action than the PPIs with extended release formulation, which is dependent on the drug half-life [23, 24]. Vonoprazan showed rapid absorption and a mean elimination half-life up to 9 h, with no apparent time-dependent inhibition of metabolism [25]. Table I shows the main characteristics responsible for P-CABs’ and PPIs’ mechanism of action differentiation.

Vonoprazan: efficacy and safety data

Efficacy and safety of vonoprazan for the management of oesophagitis related to GERD and among patients with low-dose aspirin- or NSAID-induced ulcer were previously assessed in several studies [26–39]. Considering the comparison with PPIs, only studies assessing vonoprazan performance against lansoprazole, which is a potent PPI, were conducted. The primary efficacy outcomes are those related to healing and maintenance. The studies report, in the majority, non-inferiority of vonoprazan to reach such treatment goals in a follow-up period up to 104 weeks [34–39]. Most of the single-arm studies were performed among patients refractory to PPIs, and the results show maintenance rates greater than 80% in a follow-up of up to 52 weeks [28, 29, 31, 32]. Table II shows a summary of the efficacy findings in studies using vonoprazan as a single arm or compared to PPIs. A randomized controlled trial showed how rapidly vonoprazan (20 mg) and lansoprazole (30 mg) could provide heartburn relief among patients with erosive oesophagitis [37]. The authors reported that the symptom was relieved significantly sooner with vonoprazan, highlighting the differences between P-CABs and PPIs previously described in this review [37]. The pattern of frequency of adverse events is similar to that of PPIs [35, 36, 38–41]. Gastrointestinal disorders (diarrhoea, abdominal distention) are the adverse events most frequently reported by system organ class and are similar in vonoprazan (18.4%) or PPI (19.1%) treatment [40]. However, the frequency of liver function abnormalities, one of the major concerns regarding P-CABs development, was low compared to lansoprazole (0% vs. 0.9%). Vonoprazan is considered safe and well-tolerated, the only concern is the slight increase in gastric endocrine cells [38]. Severe drug-related adverse events were not reported with vonoprazan treatment [40]. Table III shows the results regarding vonoprazan safety profile.


Vonoprazan is a new drug of the P-CABs class approved for the management of acid-related diseases in Brazil. Considering the difficulties encountered in attaining effective symptomatic control, such as night-time reflux, acidic residual reflux, and others, using currently available PPIs, this new class of drugs, which achieves rapid, potent, and prolonged acid suppression (including in the night-time), suggests meeting some unmet clinical needs in GERD treatment. According to the current reviewed material, vonoprazan is a valuable tool for managing these conditions while maintaining a comparably known safety profile to PPIs.


Medical writing support was provided by Ana Carolina Padula and Roberta Arinelli from Origin Health Company.

Conflict of interest

GD and JPPMF have received fees as speakers for Takeda. DC has received fees as an advisory board member for Takeda. JTS and MP are Takeda Pharmaceuticals Brazil full-time employees.

Takeda Pharmaceuticals Brazil funded this work.


1. Mejia A, Kraft WK. Acid peptic diseases: pharmacological approach to treatment. Expert Rev Clin Pharmacol 2009; 2: 295-314.
2. Di Mario F, Goni E. Gastric acid secretion: changes during a century. Best Pract Res Clin Gastroenterol 2014; 28: 953-65.
3. Dirac MA, Safiri S, Tsoi D, et al. The global, regional, and national burden of gastro-oesophageal reflux disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 2020; 5: 561-81.
4. Moraes-Filho JPP, Chinzon D, Eisig JN, et al. Prevalence of heartburn and gastroesophageal reflux disease in the urban Brazilian population. Arq Gastroenterol 2005; 42: 122-7.
5. do Rosario Dias de Oliveira Latorre M, Medeiros da Silva A, Chinzon D, et al. Epidemiology of upper gastrointestinal symptoms in Brazil (EpiGastro): a population-based study according to sex and age group. World J Gastroenterol 2014; 20: 17388-98.
6. Ribeiro AQ, Sevalho G, Cesar CC. The use of nonsteroidal anti-inflammatory drugs and the occurrence of gastric lesions among patients undergoing upper endoscopy in a university hospital in Brazil. Clinics 2006; 61: 409-16.
7. Federação Brasileira de Gastroenterologia. Refluxo gastroesofágico: diagnóstico e tratamento. Projeto Diretrizes. São Paulo: AMB; CFM; 2003. 18.
8. World Gastroenterology Organisation (WGO). Perspectiva mundial sobre a doença do refluxo gastroesofágico. In: World Gastroenterology Organisation Global Guidelines DRGE. 2015; 1-38.
9. Federação Brasileira de Gastroenterologia. Úlcera Péptica. Projeto Diretrizes. São Paulo: AMB; CFM 2003; 12.
10. The National Institute for Health and Care Excellence (NICE). Managing peptic ulcer disease in adults. Vol. 37, NICE Pathways. 2020. p. 56hn1–4.
11. Zaterka S, Marion SB, Roveda F, et al. Historical perspective of gastroesophageal reflux disease clinical treatment. Arq Gastroenterol 2019; 56: 202-8.
12. Martinucci I, Blandizzi C, Bodini G, et al. Vonoprazan fumarate for the management of acid-related diseases. Expert Opin Pharmacother 2017; 18: 1145-52.
13. 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: 79-94.
14. Hunt RH, Scarpignato C. Potassium-competitive acid blockers (P-CABs): are they finally ready for prime time in acid-related disease? Clin Transl Gastroenterol 2015; 6: e119-4.
15. Inatomi N, Matsukawa J, Sakurai Y, Otake K. Potassium-competitive acid blockers: advanced therapeutic option for acid-related diseases. Pharmacol Ther 2016; 168: 12-22.
16. Garnock-Jones KP. Vonoprazan: first global approval. Drugs 2015; 75: 439-43.
17. Ministério da Saúde (Brasil). Agência Nacional de Vigilância Sanitária. (ANVISA). Registro ANVISA no 1063902820056 – INZELM [Internet]. 2021 [cited 2021 Apr 28]. Available from: https://www.smerp.com.br/anvisa/?ac=prodDetail&anvisaId=1063902820056
18. Yang X, Li Y, Sun Y, et al. Vonoprazan: a novel and potent alternative in the treatment of acid-related diseases. Dig Dis Sci 2018; 63: 302-11.
19. 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-methylmethanamine fumarate (tak-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem 2012; 55: 4446-56.
20. Kiyotoki S, Nishikaa J, Sakaida I. Efficacy of vonoprazan for Helicobacter pylori eradication. Intern Med 2020; 59: 153-61.
21. Rawla P, Sunkara T, Ofosu A, Gaduputi V. Potassium-competitive acid blockers – are they the next generation of proton pump inhibitors? World J Gastrointest Pharmacol Ther 2018; 9: 63-8.
22. New drug approved for market in China in 2019: TAK-438, Vonoprazan fumarate [Internet]. [cited 2021 Jul 15]. Available from: https://www.chinazerchem.com/news/characteristics-of-food-additives-27520879.html
23. Scarpignato C, Hunt RH. The potential role of potassium-competitive acid blockers in the treatment of gastroesophageal reflux disease. Curr Opin Gastroenterol 2019; 35: 344-55.
24. Shibli F, Kitayama Y, Fass R. Novel therapeies for gastroesophageal reflux disease: beyond proton pump inhibitors. Curr Gastroenterol Rep 2020; 22: 16.
25. 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: 636-48.
26. 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; 6: 1-10.
27. Kagami T, Sahara S, Ichikawa H, et al. Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype. Aliment Pharmacol Ther 2016; 43: 1048-59.
28. Mizuno H, Nishino M, Yamada K, et al. Efficacy of vonoprazan for 48-week maintenance therapy of patients with healed reflux esophagitis. Digestion 2020; 101: 411-21.
29. Mizuno H, Yamada K, Minouchi K, et al. Efficacy of vonoprazan for 24-week maintenance therapy of patients with healed reflux esophagitis refractory to proton pump inhibitors. Biomed Rep 2018; 8: 148-55.
30. Umezawa M, Kawami N, Hoshino S, et al. Efficacy of on-demand therapy using 20-mg vonoprazan for mild reflux esophagitis. Digestion 2018; 97: 309-15.
31. Tanabe T, Hoshino S, Kawami N, et al. Efficacy of long-term maintenance therapy with 10-mg vonoprazan for proton pump inhibitor-resistant reflux esophagitis. Esophagus 2019; 16: 377-81.
32. Hoshino S, Kawami N, Takenouchi N, et al. Efficacy of Vonoprazan for proton pump inhibitor-resistant reflux esophagitis. Digestion 2017; 95: 156-61.
33. Ochiai Y, Iizuka T, Hoshihara Y, et al. Efficacy of vonoprazan for refractory reflux esophagitis after esophagectomy. Dig Dis 2021; 39: 2753.
34. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296: 2947-53.
35. Mizokami Y, Oda K, Funao N, et al. Vonoprazan prevents ulcer recurrence during long-term NSAID therapy: randomised, lansoprazole-controlled non-inferiority and single-blind extension study. Gut 2018; 67: 1042-51.
36. Ashida K, Iwakiri K, Hiramatsu N, et al. Maintenance for healed erosive esophagitis: phase III comparison of vonoprazan with lansoprazole. World J Gastroenterol 2018; 24: 1550-61.
37. Oshima T, Arai E, Taki M, et al. Randomised clinical trial: vonoprazan versus lansoprazole for the initial relief of heartburn in patients with erosive oesophagitis. Aliment Pharmacol Ther 2019; 49: 140-6.
38. 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: 240-51.
39. Ashida K, Sakurai Y, Nishimura A, et al. Randomised clinical trial: a dose-ranging study of vonoprazan, a novel potassium-competitive acid blocker, vs. lansoprazole for the treatment of erosive oesophagitis. Aliment Pharmacol Ther 2015; 42: 685-95.
40. Xiao Y, Zhang S, Dai N, et al. Phase III, randomised, double-blind, multicentre study to evaluate the efficacy and safety of vonoprazan compared with lansoprazole in Asian patients with erosive oesophagitis. Gut 2020; 69: 224-30.
41. Kawai T, Oda K, Funao N, et al. Vonoprazan prevents low-dose aspirin-associated ulcer recurrence: randomised phase 3 study. Gut 2018; 67: 1033-41.
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