Potent Potassium-competitive Acid Blockers: A New Era for the Treatment of Acid-related Diseases

Abstract

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.

Keywords: Anti-inflammatory agents, non-steroidal; Esophagitis; H+, K+-exchanging ATPase; Helicobacter pylori; Potassium-competitive acid blocker.

Figure 1

Chemical structure of vonoprazan.

Figure 2

Comparison of mechanisms of action of lansoprazole (conventional proton pump inhibitor) and vonoprazan (potassium-competitive acid blocker). Hydrogen potassium (H⁺, K⁺)-ATPases are located in tubulovesicles in quiescent phage and appear on the apical membrane of secretory canaliculus in the active phase, which occurs after a meal. Lansoprazole converts to its active form in the secretory canaliculus, though it degrades soon after (X). The active form of lansoprazole covalently binds to H⁺, K⁺-ATPase (proton pump). Vonoprazan stably accumulates in the acidic secretory canaliculus and non-covalently binds to H⁺, K⁺-ATPase with very a very slow dissociation rate and can inhibit newly exposed H⁺, K⁺-ATPase for a long time.

Figure 3

Eradication rate of Helicobacter pylori with vonoprazan and proton pump inhibitor (PPI). The H. pylori eradication rates by first-line triple therapies from randomized controlled trials are separately shown in clarithromycin (CAM)-sensitive and CAM-resistant subgroups. NS, not significant; VAC, vonoprazan + amoxicillin + clarithromycin; LAC, lansoprazole + amoxicillin + clarithromycin; PAC; PPI (lansoprazole, rabeprazole, or esomeprazole) + amoxicillin + clarithromycin.

Figure 4

Healing rate of erosive esophagitis with vonoprazan (VPZ) and lansoprazole (LPZ) at week 2. Healing rates of erosive esophagitis with 20 mg VPZ and 30 mg LPZ at week 2 are separately shown in Los Angeles (LA) classification Grade A/B and C/D subgroups.