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Conventional proton pump inhibitors (PPIs) are used as a first-line therapy to treat acid-related diseases worldwide. However, they have a number of limitations including slow onset of action, influence by cytochrome P450 polymorphisms, unsatisfactory effects at night, and instability in acidic conditions. Alternative formulations of conventional PPIs have been developed to overcome these problems; however, these drugs have only introduced small advantages for controlling acid secretion compared to conventional PPIs. Potassium-competitive acid blockers (P-CABs) were developed and have beneficial effects including rapid, long-lasting, and reversible inhibition of the gastric hydrogen potassium ATPase, the proton pump of the stomach. Vonoprazan was recently innovated as a novel, orally active P-CAB. It is currently indicated for the treatment of gastric and duodenal ulcers, reflux esophagitis, and prevention of low-dose aspirin- or nonsteroidal anti-inflammatory drug-related gastric and duodenal ulcer recurrence in Japan. Vonoprazan does not require enteric coating as it is acid-stable, and it can be taken without food because it is quickly absorbed. Vonoprazan accumulates in parietal cells under both acidic and neutral conditions. It does not require an acidic environment for activation, has long-term stability at the site of action, and has satisfactory safety and tolerability. Thus, vonoprazan may address the unmet medical need for the treatment of acid-related diseases.
Proton pump inhibitors (PPIs) have often been used for acid-related diseases including gastroesophageal reflux disease (GERD), gastric and duodenal ulcers, non-steroidal anti-inflammatory drug (NSAID)-associated ulcers, and
To overcome the aforementioned unmet needs, alternative formulations of conventional PPIs and new H+, K+-ATPase inhibitors have been established. With these efforts, vonoprazan (TAK-438), a potassium-competitive acid blocker (P-CAB), was developed. It was found to have satisfactory effects and a good safety profile in clinical studies of gastric and duodenal ulcers, reflux esophagitis, NSAID-associated ulcers, and
Immediate-release omeprazole and dexlansoprazole modified release (MR), which improve nocturnal acid breakthrough (NAB), have been introduced as alternative formulations of PPIs in some countries.16,17 Dexlansoprazole MR is the R-enantiomer of lansoprazole and is a PPI with dual delayed-release formulation.18 The dual release system in the duodenum and small intestine achieved 2 peak concentrations within 2 hours and 5 hours after administration.19 Percentage time 24-hour intragastric pH above 4 of dexlansoprazole MR 60 mg and lansoprazole 30 mg once daily for 5 days administration was 71% and 60%, respectively (
P-CABs were first developed in the 1980s,21 and have been studied by many pharmaceutical companies worldwide, as they rapidly, effectively, and reversibly inhibit the proton pump (H+,K+-ATPase α subunit).22 However, P-CABs such as the imidazopyridine compound SCH28080 from Schering-Plough Corporation have an imidazopyridine ring that correlated with hepatic toxicity in human clinical studies and did not show superior effects compared to conventional PPIs. Imidazopyridine derivatives including AR-H047108,23–25 and linaprazan (AZD0865), imidazonaphthyridine derivatives including soraprazan,26 pyrimidine derivatives including revaprazan (YH1885), and pyrrole derivatives including vonoprazan (TAK-438) (Fig. 1) were also developed. However, only revaprazan and vonoprazan are currently on the market (Table 2). A concentration of up to 75 mg linaprazan provided similar efficacy to 40 mg esomeprazole for the healing of reflux esophagitis and controlling of heartburn.27 However, linaprazan did not provide more clinical benefits than 20 mg esomeprazole for the management of GERD.28 Because linaprazan had similar effects to esomeprazole but caused hepatic toxicity, its development was discontinued. Revaprazan is only available in South Korea and India, and is used for the treatment of peptic ulcers but not for GERD. Revaprazan rapidly inhibits gastric acid secretion but intragastric pH could only be increased to a maximum of 5 at the dosage used.29 The P-CAB YH4808 was developed in Korea; dosage ≥ 200 mg produces a rapid, sustained suppression of gastric secretion with good tolerability.30 The twice-daily use of YH4808 is more effective, especially at night, than the same dose used once-daily.30 However, this compound is still not available clinically. Other agents, DWP14012, and 1-(5-(1H-indol-5-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine (KFP-H008), P-CABs, are under development.31,32 Tegoprazan is another potent P-CAB33 that was successfully tested in a phase III trial in Korea and will be released to the market in 2018 (Table 2). A compound that has a pyrrole derivative in the center was found through high-throughput screening.34 After modifying the compound to reduce hepatic toxicity and influence of CYP2C19 polymorphism, vonoprazan was developed.35
Vonoprazan is a novel, orally active P-CAB that binds and inhibits H+, K+-ATPase at the final step in the acid secretory pathway in gastric parietal cells, and it has different mechanisms of action than conventional PPIs. It can inhibit the proton pump, even in neutral environments with an inhibitory constant (Ki) of 10 nM at pH 7 and of 3 nM at pH 6.5.36 It has stronger potential to inhibit the gastric proton pump than another P-CAB, SCH28080, and lansoprazole. The half-maximal inhibitory concentrations of vonoprazan, SCH28080, and lansoprazole were 0.018 nM, 0.14 nM, and 7.6 μM, respectively.36 The half-life (T1/2) of vonoprazan dissociation by potassium chloride was 12.5 hours in isolated proton pumps, and that of SCH28080 was less than 2 minutes. Therefore, vonoprazan has high affinity and slow clearance from gastric parietal cells, accumulating in both resting and stimulated conditions.37,38 The acid dissociation constant of vonoprazan is 9.37, which is higher than that of conventional PPIs and other P-CABs.39
When vonoprazan is exposed to acidic conditions, it is instantly protonated and remains stable. It can accumulate, function, and bind the proton pump of gastric parietal cells in strongly acidic secretory canaliculi. Vonoprazan binds −10 Å from the ion binding site that is close to the middle of the membrane domain of H+, K+-ATPase. Hydrogen bonding between Tyr799 and the sulfone of vonoprazan was suggested.36 The dissociation rate of vonoprazan from H+, K+-ATPase is slow and acid does not decomposed it. Non-ionic type of vonoprazan is decreased in a strong acidic secretory canaliculi and passive transport from the acidic secretory canaliculus to the cytoplasm is inhibited. It is therefore retained for a long time inside the parietal cells and can inhibit H+, K+-ATPase that is activated by further stimulation of acid secretion (Fig. 2).15,36,40 The concentration of vonoprazan is up to 108-fold higher in the secretory canaliculus of the parietal cell than in the plasma. It can stay in the protonated form, and binds to the H+, K+-ATPase α subunit to compete with potassium binding, and inhibits the function of the pump.41 The binding of vonoprazan to the proton pump is ionic, and its effects are reversible and dose-dependent.
Conventional PPI is a form of prodrug, which must be protonated to become an active form. To achieve this protonation process, the PPI should be reached in parietal cells in which acid secretion must be activated after the meal. Considering the time taken for this process, 30 minutes before the meal is required.42 However, vonoprazan can be taken regardless of meal ingestion and the rate of absorption is not affected by meals.15 The absorption speed of vonoprazan is rapid, and the time taken to reach maximum concentration in plasma is less than 2 hours after oral administration.43 After absorption, the T1/2 in plasma is approximately 2 hours for conventional PPIs, but up to 9 hours for vonoprazan.44 Therefore, vonoprazan stays in the blood longer and can block acid secretion continuously.45 The pharmacokinetics of vonoprazan are similar in Japanese and non-Japanese subjects.45,46
The CYP2C19 polymorphism influences the pharmacokinetics of conventional PPIs and affects interindividual variability in pharmacodynamics.47 However, because vonoprazan is not primarily metabolized by CYP2C19,44 the data from clinical studies on healthy volunteers and GERD patients showed limited influence by CYP2C19 polymorphisms.35,45,46,48,49 Furthermore, the effects of clarithromycin, a potent CYP3A4 inhibitor, on the pharmacokinetics of vonoprazan were evaluated and no significant pharmacokinetic interactions were observed.50
Vonoprazan is effectively absorbed and quickly accumulates in parietal cells. In contrast, conventional PPIs require 3 to 5 days to achieve maximal and steady-state inhibition of acid secretion.7,51 The effect is more pronounced after the first dose of vonoprazan compared to conventional PPIs; a single dose of 20 mg vonoprazan can increase intragastric pH to nearly 7 in as little as 4 hours.46 This rapid onset of action is appropriate for the treatment of breakthrough GERD symptoms and for on-demand therapy. Furthermore, % time 24-hour intragastric pH above 4 of vonoprazan 20 mg once daily for 4 days and 7 days was 82.9% and 85.2%, respectively46 and the effect continues without intragastric pH dipping below 4. The means of night-time pH above 4 after administration of vonoprazan 20 mg on day 1 were higher than after administration of esomeprazole 20 mg or rabeprazole 10 mg (Table 1).48 Once this pH is maintained through daily administration, the pepsin produced by chief cells cannot be activated. Therefore, vonoprazan is a strong acid blocker that has rapid, stable, and long-lasting effects35,46,48,52 and these effects were stronger than conventional PPIs35,41,45,48,52,53 and prototype P-CAB.41 Phase I studies of single ascending45 and multiple repeat doses46 in Japan and the United Kingdom revealed that vonoprazan was well-tolerated at single doses of 1–120 mg and at repeat doses of 10–40 mg.54 The mean percentage of time that patients had a intragastric pH above 4 after multiple doses of 40 mg vonoprazan was 85.3% and 100.0% during the day and 86.5% and 100.0% at night (21:00–9:00) on days 1 and 7, respectively.46
Both prospective and retrospective studies have shown that the
The eradication rate with vonoprazan-based triple therapy was also better than PPI-based triple therapy in young and middle age groups, indicating that strong acid inhibition is more effective in young than in old patients who may have less acid secretion with severe atrophic changes in gastric mucosa.69 The effects of vonoprazan for the second-line treatment of
GERD is one of the most common esophageal diseases, characterized by symptoms of heartburn and acid regurgitation due to reflux of the stomach contents. The prevalence of GERD diagnosed by heartburn and/or acid regurgitation symptoms in East Asia is 2.5–7.8%.79,80 The impact of GERD on quality of life (QOL) is large, and GERD is a burden on healthcare systems.81,82 The major goals of treating erosive esophagitis are to relieve symptoms, heal erosions, and prevent complications.83 Although host factors might exist because not all patients have abnormal gastroesophageal reflux, gastric acid is the principle factor underlying the development of reflux esophagitis, and PPIs have been the gold standard for treatment in the clinical setting.3,84,85 Intragastric pH above 4 holding time has been used to show the effects of acid-suppressive drugs, because erosive esophagitis can be controlled and healed when this time is long.86 However, the degree of acid suppression by PPIs is not complete and no data have shown that a pH of 4 is enough to control reflux symptoms. Furthermore, approximately 80% of patients with frequent heartburn experience heartburn at night, and 29% of those are awakened by coughing or choking due to gastroesophageal reflux at night.87,88 Nighttime acid reflux with NAB influences sleep quality and daytime QOL. More than 30% of patients on PPIs due to reflux esophagitis with heartburn continuously experience nocturnal heartburn;89 therefore, this issue is one of the unmet clinical needs. More than 50% of symptomatic GERD patients taking PPIs are not satisfied with the treatment, and more than 20% of patients take PPIs twice daily or purchase medicines over the counter in addition to their prescribed medicine.90
The safety and dose–response profiles of vonoprazan were evaluated in an 8-week phase II study. Patients with erosive esophagitis were treated at doses of 5, 10, 20, and 40 mg once daily for 8 weeks and compared to those who were treated with 30 mg lansoprazole once daily for 8 weeks. Vonoprazan was effective and noninferior to lansoprazole for curing erosive esophagitis.49 Although the study was designed to show the noninferiority of vonoprazan to lansoprazole, the healing rate of severe esophagitis (Los Angeles [LA] classification, Grades C/D) with 20 mg vonoprazan was higher than that with 30 mg lansoprazole at week 2 (96.0% vs 82.6%) (Fig. 4). In another phase II study, the noninferiority of 20 mg vonoprazan compared to 30 mg lansoprazole for treating erosive esophagitis was confirmed and the long-term efficacy of vonoprazan was evaluated.91 In post hoc analyses, patients with severe esophagitis (LA Grades C/D) or with extensive CYP2C19 metabolism experienced better treatment effects in the vonoprazan group than in the lansoprazole group (Table 1). Long-term (52 weeks) maintenance treatment of 10 mg or 20 mg vonoprazan resulted in less than 10% erosive esophagitis recurrence and vonoprazan was well-tolerated overall. Vonoprazan was also assessed for the treatment of refractory GERD compared to conventional PPI. In an open label study, vonoprazan was effective for the treatment of PPI (standard single-dose)-refractory symptomatic GERD (Table 1).92 Because this was an open label study, potential bias may have existed. However, the symptoms were quickly relieved in the study, and this effect might have correlated with the potent inhibition of acid production from the first dose of vonoprazan. Doses of 20 mg and 40 mg vonoprazan significantly inhibited gastric acid secretion after 24 hours and treated erosive esophagitis that was resistant to standard dose of conventional PPIs (Table 1).93 Further studies are warranted to prove the rapid relief of GERD symptoms by vonoprazan.
Randomized, controlled trials confirmed the noninferiority of vonoprazan for the 8-week treatment of gastric ulcer (93.5% and 93.8% for vonoprazan and lansoprazole, respectively).94 However, the noninferiority of vonoprazan compared to lansoprazole for the 6-week treatment of duodenal ulcer was not confirmed in the trial (95.5% and 98.3% for vonoprazan and lansoprazole, respectively). The factors that affected these data might have correlated with dropout subjects who did not complete the study and were counted as non-healed subjects. Some of the subjects might have stopped the study because their symptoms were quickly relieved by vonoprazan or lansoprazole. Further studies are needed to conclude the efficacy of vonoprazan for the treatment of gastric and duodenal ulcers.
NSAIDs cause gastrointestinal (GI) ulcers and increase the risk of serious GI complications.95 Risk factors associated with the occurrence of NSAID-related ulcers are history of GI ulcer with bleeding, concomitant use of two or more NSAIDs/low-dose aspirin (LDA), high dose of NSAIDs, concomitant use of anticoagulant agent, history of gastric and duodenal ulcers, age over 70 years, and
A meta-analysis showed that PPIs significantly reduced the risk of NSAID-associated ulcers compared to placebo, and NSAIDs plus PPI was the most cost-effective strategy for preventing upper GI ulcers in patients on long-term NSAID therapy.102 A dose of 20 mg esomeprazole once daily was effective and safe for preventing NSAID-associated upper GI ulcer recurrence.103 Because NSAID-associated upper GI injury is pH-dependent, the higher the in-tragastric pH, the lower the incidence of injury.104,105 Vonoprazan strongly inhibits acid production from the first dose. No clinically meaningful interactions during concomitant use of vonoprazan and NSAIDs were observed, and vonoprazan was well-tolerated when administered with LDA or NSAIDs.106 Therefore, the efficacy and safety of vonoprazan for preventing NSAID-associated upper GI ulcer recurrence has been evaluated in patients continuously receiving NSAIDs in double-blind, randomized trials.107 Vonoprazan (10 mg and 20 mg) was effective for NSAID-associated upper GI secondary ulcer prevention. These results were consistent with previous studies that investigated the effect of PPIs in NSAID-associated secondary ulcer prevention.103,108,109 No unexpected adverse events were identified during at least a 1-year period of exposure to vonoprazan. After these data were introduced, the Japanese government approved 10 mg vonoprazan for the prevention of recurrent upper GI ulcers during long-term NSAID therapy.
The efficacy and safety of vonoprazan for preventing recurrent upper GI ulcer in patients with long-term LDA therapy was evaluated in a phase III study.110 The rate of gastric and duodenal ulcer recurrence after 24 weeks of LDA therapy was 2.8%, and was 0.5% with 15 mg lansoprazole or 10 mg vonoprazan. Thus, 10 mg vonoprazan is as effective as 15 mg lansoprazole for preventing recurrent upper GI ulcer during LDA therapy.110 Vonoprazan treatment resulted in lower ulcer recurrence rates and upper GI bleeding compared to lansoprazole during long-term LDA treatment. Vonoprazan has long-term safety (at least 24 weeks) and is well-tolerated.
The more acid that is secreted, the more that effective acid suppression is needed, and the more the effects of vonoprazan stand out. When vonoprazan is used for short-term acid suppression, there are no problematic side effects. However, when long-term acid suppression treatment is needed, side effects such as hypergastrinemia, pneumonia, small bowel bacterial overgrowth, and
In conclusion, vonoprazan is superior to conventional PPIs for suppressing acid secretion, especially at night, and there was no difference in efficacy depending on CYP2C19 genotype status. In addition, vonoprazan was shown to overcome the weaknesses associated with conventional PPIs. The advantages of vonoprazan compared to previous P-CABs are that it does not have the hepatic toxicity observed with previous P-CABs, and it has slow dissociation from H+, K+-ATPase while its actions are long-lasting. In clinical trials, vonoprazan showed potent acid-suppressive effects, and rapid and long-lasting effects for the treatment of acid-related diseases including reflux esophagitis, LDA/NSAID-associated ulcer recurrence, and