Acid-related diseases (ARDs), which include gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), and Helicobacter pylori infections, continue to be a major healthcare concern despite advances in management strategies (Inatomi et al., 2016). ARD management primarily involves gastric acid suppression, with current options including proton pump inhibitors (PPIs) that covalently and irreversibly bind to H⁺-K⁺-ATPase (Oshima and Miwa, 2018). PPIs have been available for more than 30 years and are considered the cornerstone treatment for patients with ARDs (Turshudzhyan et al., 2022). However, PPIs: 1) only bind to active proton pumps, 2) have a short half-life, 3) are influenced by food intake, 4) have a relatively slow onset action requiring 3–5 days of dosing for the optimal acid suppression, and 5) show high interindividual variability in pharmacokinetics (PK) due to genetic polymorphism of hepatic cytochrome P4502C19 (CYP2C19) (Sachs et al., 2007; Otake et al., 2016; Buzas and Birinyi, 2023; Katzka and Kahrilas, 2023). These limitations contribute to the inability of PPIs to maintain a prolonged increased intragastric pH critical for mucosal healing in patients with erosive esophagitis (EE) and the eradication of H. pylori (Buzas and Birinyi, 2023; Scarpignato et al., 2023). In the management of ARDs, the percentage of time intragastric pH is above 4 (pH > 4 holding time ratio [HTR]) should be more than 75% within 24 h for healing EE, while prolonged pH 6 HTR >75% is required for optimum H. pylori eradication since bacterial replication is active. Antibiotic effectiveness is optimized in this environment (Scarpignato et al., 2023; Yaozong, 2023). Based on published literature, PPIs have a 24-h intragastric pH 4 HTR of up to 65.1% with once-daily dosing and pH 6 HTR of up to 69% with twice-daily dosing at day 7, which may not be adequate in achieving the standard pH HTR required for EE healing and H. pylori eradication (Sakurai et al., 2015a; Kagami and Furuta, 2016).

Meanwhile, potassium-competitive acid blockers (P-CABs) bind to the K⁺ site of H⁺/K⁺ ATPase to block access of the K⁺ ion to the proton pump to prevent H⁺ secretion; they form non-covalent and reversible bonds with H⁺-K⁺-ATPase and competitively bind to both active and inactive proton pumps in a K⁺-competitive manner (Inatomi et al., 2016; Otake et al., 2016). Unlike PPIs, P-CABs have different structures compared with PPIs, are acid stable, and do not require enteric coating. P-CABs are also not dependent on food intake, are not prodrugs, and have long half-lives. These properties result in more rapid attainment of peak plasma levels with potent and consistent onset of acid suppression, irrespective of CYP2C19, compared with PPIs (Inatomi et al., 2016; Sugano, 2018; Leowattana and Leowattana, 2022; Wong et al., 2022; Buzas and Birinyi, 2023).

Six P-CABs are currently approved and available in clinical practice for different indications: revaprazan, vonoprazan, tegoprazan, fexuprazan, keverprazan, and zastaprazan. Meanwhile, clinical trials are ongoing for X842 (Leowattana and Leowattana, 2022; Blair, 2024; Scarpignato and Hunt, 2024). Each of these P-CABs has different pharmaceutical structures as well as PK and pharmacodynamic (PD) characteristics that may translate to different clinical properties. This narrative review provides an overview of these currently available P-CABs for managing patients with ARD. The structure, PK and PD properties, clinical efficacy, and safety of P-CABs in patients with ARD are also compared, to guide daily clinical practice.

This narrative review involved a comprehensive search of available publications on P-CABs in ARDs from 1 January 2002 to 15 June 2024 using PubMed, Embase, and clinical trial registration websites, as well as press releases and product labeling, and summarized key PK and PD properties, clinical efficacy, and safety profile to provide a reference for clinical practice. Study selection was limited to articles in English involving human subjects. The following filters were applied: Clinical Study, Clinical Trial, Meta-analysis, Systematic Review, Randomized Clinical Trial, and Practice Guideline.

To ensure comprehensive coverage, detailed search terms for drug names, disease conditions, and related interventions were used. See the Supplementary Appendix for the full list of search terms used.

An overview of the differences in structures and PK and PD properties of currently available P-CABs are provided in Figure 1 and Supplementary Table S1.

First, revaprazan has a pyrimidine structure and PK properties of plasma peak (T_max) at 1.3–2.5 h after a single dose of up to 200 mg, with a mean elimination time (T_1/2) of 2.2–2.4 h (Leowattana and Leowattana, 2022). Regarding PD, the 24-h intragastric pH 4 HTR for revaprazan at 200 mg was 25.1% on day 1 after a single dose and 25.3% on day 7 after multiple doses (Sunwoo et al., 2020). Although it can rapidly inhibit gastric acid secretion, revaprazan has only been able to increase intragastric pH up to 5 (Oshima and Miwa, 2018).

Vonoprazan has a pyrrole structure and lacks the imidazopyridine ring common in other P-CABs. It has a high negative log of the acid dissociation constant (pKa) of 9.3, which makes it a basic compound that remains un-ionized in the acidic canaliculi of the gastric parietal cells and is expected to bind to proton pumps regardless of acid secretion. Its median T_max ranges from 1.5 to 2.0 h for 10–40 mg once daily (QD). It has a mean T_1/2 of up to 9 h, which means that vonoprazan can stay in the blood longer and block acid secretion continuously (Jenkins et al., 2015). In terms of PD, vonoprazan 20 mg QD also has a rapid and sustained acid-inhibitory effect, with means 24-h intragastric pH 4 HTRs of 84.2% on day 1 and 93.8% on day 7 (Sakurai et al., 2015a). Studies have also shown that the 24-h intragastric pH 6 HTRs for vonoprazan 20 mg QD and 20 mg twice daily (BID) were 74% and 85%, respectively (Kagami and Furuta, 2016). These properties collectively contribute to vonoprazan’s improved potency and durability of acid suppression compared to PPIs and other P-CABs (Supplementary Table S1) (Jenkins et al., 2015; Srinivas, 2016).

Fexuprazan also has a pyrrole structure like vonoprazan (Leowattana and Leowattana, 2022). It has a T_max of 1.75–3.5 h with single doses of 10–320 mg and a T_1/2 of 9.1 h with the standard 40 mg dose. At 40 mg QD, fexuprazan has 24-h intragastric pH 4 HTRs of 44.6% on day 1 and 55.7% on day 7 (Sunwoo et al., 2018; Daewoong, 2022).

Tegoprazan has a benzimidazole structure and a pKa of 5.1, T_max of 1.84 h (0.83–3.00 h) after a single dose of 50 mg, and T_1/2 of about 4.1 h (Han et al., 2023; Scarpignato and Hunt, 2024). The 24-h intragastric pH 4 HTR of tegoprazan 50 mg QD was 58.55% (Han et al., 2023).

Keverprazan has an imidazopyridine structure, a T_max of 1.25–1.75 h, and T_1/2 ranging from 6.00 to 7.17 h from 5 to 60 mg QD (Zhou et al., 2023b). At 20 mg QD, keverprazan had 24-h intragastric pH 4 HTRs on days 1 and 7 of 85.0% and 98.3%, respectively (Zhou et al., 2023a).

Zastaprazan also has an imidazopyridine structure. At 5–60 mg, zastaprazan has a T_max of 0.5–1.5 h and T_1/2 of 6–9 h. Zastaprazan 20 and 40 mg had 24-h intragastric pH 4 HTRs of 85% and 92%, respectively (Blair, 2024).

P-CABs provide a viable alternative to PPIs in the management of patients with ARD by overcoming the limitations associated with PPIs (Inatomi et al., 2016; Katzka and Kahrilas, 2023). In particular, the superior PK and PD properties of P-CABs with respect to acid suppression—rapid and potent acid suppression, minimal interindividual variability in acid control, and sustained efficacy (i.e., prolonged HTRs at higher pH levels) after a single dose vs. PPIs—potentially make them a preferable option for ARD management (Sakurai et al., 2015b; Otake et al., 2016; Sugano, 2018; Buzas and Birinyi, 2023; Katzka and Kahrilas, 2023; Scarpignato et al., 2023). As demonstrated in the reviewed clinical studies (Supplementary Table S2), P-CABs have comparable or superior clinical efficacy and generally comparable safety as PPIs across different ARD indications. In particular, vonoprazan appears as the most established P-CAB due to its robust clinical trial evidence, and it is currently acknowledged by several treatment guidelines for the treatment of GERD (Jung et al., 2021; Xiao et al., 2021; Iwakiri et al., 2022) and H. pylori eradication (as a component of quadruple-, triple-, and dual-therapy regimens) (Kato et al., 2019; Malfertheiner et al., 2022; Zhou et al., 2022; Chey et al., 2024), and PUD (Kamada et al., 2021). Meanwhile, preliminary PK and PD studies indicate that the newer P-CABs keverprazan and zastaprazan have also achieved acid suppression levels comparable to vonoprazan, suggesting strong potency across this drug class (Zhou et al., 2023a; Blair, 2024). Nevertheless, it should be emphasized that in this review, all other available P-CABs, including fexuprazan, keverprazan, revaprazan, tegoprazan, and zastaprazan, have demonstrated at least non-inferiority to PPIs in randomized clinical trials across various ARDs.

To appreciate the efficacy of P-CABs in ARD management and, in particular, the potential clinical advantages of vonoprazan vs. other P-CABs, it is important to identify the key differences in the PK and PD properties between vonoprazan and other available P-CABs, which are summarized in Supplementary Table S1.

In GERD, achieving mucosal healing is related to the degree and duration of acid suppression and the length of treatment, which may also help achieve effective symptomatic control that may be challenging with current PPIs (Scarpignato and Hunt, 2024). Although PPIs are considered first-line treatment for GERD, first-line P-CABs—specifically, vonoprazan and tegoprazan—have been recognized as valid options due to their demonstrated efficacy and safety in GERD clinical trials (Jung et al., 2021; Xiao et al., 2021; Iwakiri et al., 2022). For instance, treatment with vonoprazan achieved up to 99.0% healing rate for patients with EE at 8 weeks and up to 98.7% for those with severe EE (LA grades C/D), whereas tegoprazan treatment achieved healing rates of up to 98.9% (Ashida et al., 2016; Lee et al., 2019).

The consistent efficacy associated with vonoprazan in EE may be attributed to its more potent and sustained acid suppression vs. other P-CABs. Initial 20 mg administration of vonoprazan exceeds the ideal 24-h intragastric pH 4 HTR threshold of >75% required for mucosal healing, especially in severe EE cases (i.e., LA grade C/D) (Supplementary Table S1) (Sakurai et al., 2015a; Zhang et al., 2022; Buzas and Birinyi, 2023; Yaozong, 2023). Across multiple phase 3 trials, vonoprazan achieved higher and faster healing rates and lower recurrence rates than PPI comparators such as lansoprazole (Ashida et al., 2016; Ashida et al., 2018; Xiao et al., 2020; Laine et al., 2023; Xiao et al., 2024). Other P-CABs have also demonstrated non-inferiority for EE healing and maintenance vs. standard PPIs, although data for severe EE are limited.

Sustained intragastric pH > 6 enhances antibiotic efficacy in H. pylori eradication, a target often unmet by PPIs but consistently reached with vonoprazan. (Malfertheiner et al., 2022; Zhang et al., 2022; Buzas and Birinyi, 2023; Scarpignato et al., 2023; Yaozong, 2023; Scarpignato and Hunt, 2024). This PD advantage is reflected in clinical trials showing that vonoprazan-based regimens consistently resulted in higher eradication rates vs. PPI-based therapy, including in clarithromycin-resistant infections (Murakami et al., 2016; Chey et al., 2022; Song et al., 2022; Peng et al., 2023). Emerging studies of other P-CABs also suggest non-inferiority for eradication compared to PPIs (Supplementary Table S2).

Published 24-h intragastric pH 6 HTRs for other P-CABs are limited, and among those with available values, only vonoprazan at the standard 20 mg BID regimen for H. pylori eradication achieves the ideal 24-h intragastric pH 6 HTR >75% (Supplementary Table S1) (Kagami and Furuta, 2016; Yaozong, 2023). In a more recent multicenter randomized trial, vonoprazan 20 mg BID plus amoxicillin 1 g TID dual therapy achieved a median pH of 7.4 on day 1 and 7.8 on day 7, with dynamic 24-h profiles showing gastric pH > 6 within 4–5 h of first dosing and maintained at pH 7 to 9 thereafter (Song et al., 2025). These findings reinforce the potent and sustained acid suppression of vonoprazan beyond earlier reports. It is also associated with prolonged nocturnal acid suppression, i.e., nocturnal pH 4 HTR of 84.3% after one dose of vonoprazan 20 mg QD (Sakurai et al., 2015a). These properties suggest that vonoprazan may have advantages over existing acid-suppressing drugs in providing early response due to the maximum efficacy after the first dose, which may help ensure increased antibiotic stability and efficacy and concomitant high H. pylori eradication rates (Jenkins et al., 2015; Scarpignato et al., 2023; Song et al., 2025).

Comparable H. pylori eradication rates were also reported for tegoprazan-based quadruple therapy and keverprazan-based quadruple therapy vs. PPI-based comparator groups (Kim et al., 2023; Tan et al., 2024; Zhou and Song, 2024). These results suggest that the benefits of P-CABs in the context of H. pylori eradication may extend to other agents in this class. However, further studies are needed to establish whether their PD properties of acid suppression vs. PPIs consistently translate into clinical efficacy in treating H. pylori infections.

Vonoprazan, tegoprazan, revaprazan, and keverprazan have generally shown comparable efficacy and safety vs. PPIs in treating gastric and duodenal ulcers (Chung et al., 2005; Chang et al., 2007; Miwa et al., 2017; Cho et al., 2020; Hou et al., 2022; Tan et al., 2023). Vonoprazan, in particular, demonstrated non-inferior healing vs. PPIs for gastric and duodenal ulcers, achieving healing rates of up to 93.8% at 8 weeks and 97.1% at 6 weeks (Miwa et al., 2017). Vonoprazan also had non-inferior (10 mg QD) and superior results (20 mg QD) vs. lansoprazole in the secondary prevention of LDA-induced PUD (Kawai et al., 2018). Tegoprazan treatment also achieved non-inferiority to lansoprazole for gastric ulcer healing, achieving up to approximately 95% healing rate at 8 weeks (Cho et al., 2020).

Collectively, these efficacy data have led to including P-CABs in multiple regional and international guidelines for GERD, H. pylori eradication, and PUD (Kato et al., 2019; Jung et al., 2021; Kamada et al., 2021; Xiao et al., 2021; Iwakiri et al., 2022; Malfertheiner et al., 2022; Zhou et al., 2022; Association. et al., 2023; Chey et al., 2024).

While the clinical efficacy of P-CABs has been demonstrated across regions, it is important to note that their approval and routine clinical use remain geographically limited. Notably, the recently published Mexican consensus guidelines for the management of GERD are among the first in Latin America to recommend P-CABs alongside PPIs as drugs of choice for both EE and NERD, as well as for patients with refractory symptoms. This inclusion reflects the growing recognition of P-CABs’ clinical value in new regions, even as regulatory approval in many countries is still pending (Valdovinos Diaz et al., 2024).

Alongside regulatory and clinical considerations, drug cost may represent a major barrier to the wider adoption of P-CABs. For instance, in North America, these agents are typically priced higher than established generic PPIs and may face inconsistent insurance coverage (pmarketresearch.com, 2024). Meanwhile, P-CABs have been demonstrated to be more cost-effective than PPIs based on several cost-effectiveness analyses in Asia (Wang et al., 2022; Miwa et al., 2023). While the health economic implications and cost-effectiveness of P-CABs vs. existing therapies are important issues, a detailed evaluation is beyond the scope of this review.

While our review includes studies published through June 2024, new clinical data on additional P-CABs are emerging. For example, a recent randomized trial in Korea established the non-inferiority of on-demand tegoprazan vs. esomeprazole for GERD (Kang et al., 2025). Results from ongoing phase 3 trials are also expected to support the efficacy of tegoprazan in patients with EE and NERD (NCT05587309, NCT05587322) (ClinicalTrials.gov, 2025a; ClinicalTrials.gov, 2025b). Similarly, prospective data also now support the efficacy and safety of fexuprazan in patients with laryngopharyngeal reflux disease (Kim et al., 2024). These findings attest to the expanding role of P-CABs as a class for managing diverse ARDs.

Overall, the safety profiles of P-CABs are broadly similar and overlap with those of PPIs across the different studies and ARD indications in this narrative review. No new safety signals were reported, and patients generally tolerated all P-CABs well. While some earlier P-CABs, such as the imidazopyridine compound SCH28080 and its derivative, linaprazan, were withdrawn due to hepatotoxicity, this adverse event was not reported in any of the clinical studies on the newer agents reviewed here (Oshima and Miwa, 2018).

Clostridium difficile infection (CDI) is a recognized complication associated with prolonged and potent gastric acid suppression, as previously observed with PPIs and, more recently, with P-CABs such as vonoprazan (Otake et al., 2016; Oshima and Miwa, 2018; Sugano, 2018; Wong et al., 2022). Although CDI was not reported in the P-CAB clinical studies included in this review, available evidence and mechanistic studies suggest that both PPIs and vonoprazan may similarly increase CDI risk, particularly with longer treatment duration or higher acid suppression (Mori and Suzuki, 2019; Saruta et al., 2023; Ouyang et al., 2024). Further studies are warranted to clarify the association between chronic vonoprazan and other P-CAB use and CDI.

Hypergastrinemia is a concern with prolonged acid suppression, which has been associated with gastric endocrine hyperplasia and increased risk of carcinoid tumor development with chronic PPI use, although long-term consequences remain unclear (Sugano, 2018). The increase in serum gastrin concentration is believed to be a consequence of the potent gastric acid antisecretory effect of PPIs, which was also demonstrated in the clinical studies on P-CABs included in this review (Murakami et al., 2016; Miwa et al., 2017; Sugano, 2018; Lee et al., 2022; Wong et al., 2022; Fass et al., 2023; Laine et al., 2023; Oh et al., 2025). Among the P-CABs reviewed, vonoprazan was notably associated with consistently greater increases in serum gastrin than with lansoprazole treatment, which may be due to its comparatively more potent gastric acid suppression vs. other P-CABs demonstrated in PK and PD studies (Sakurai et al., 2015a; Ashida et al., 2016; Inatomi et al., 2016; Kagami and Furuta, 2016; Ashida et al., 2018). Keverprazan and zastaprazan were the only other P-CABs demonstrated to have greater serum gastrin increases vs. their comparator PPIs, consistent with their comparable pH 4 HTRs with vonoprazan (Tan et al., 2023; Zhou et al., 2023a; Blair, 2024; Oh et al., 2025).

Despite the associated hypergastrinemia observed with P-CAB treatment, no adverse clinical effects or significant gastric mucosal changes were reported in the clinical trials reviewed. Gastrin levels also consistently returned to baseline after cessation of therapy (Murakami et al., 2016; Miwa et al., 2017). Notably, even with extended vonoprazan administration of up to 104 weeks in the trial on LDA-associated PUD prevention, no gastric endocrine cell tumors were reported, despite associated increases in gastrin levels (Kawai et al., 2018). This was further supported by the results of the 5-year VISION study in patients with EE. Findings revealed that while maintenance therapy with vonoprazan 10 mg QD was associated with higher gastrin, parietal cell hyperplasia, and foveolar hyperplasia than maintenance lansoprazole 10 mg QD, no increased risk of malignant epithelial alterations or gastric neuroendocrine tumors was observed. The VISION trial is the only study to date providing 5-year safety data for a P-CAB (Uemura et al., 2018; Uemura et al., 2025). Nevertheless, further long-term safety data remain essential as more potent P-CABs and broader indications emerge (Wong et al., 2022; Scarpignato and Hunt, 2024).