A Study Comparing the Antisecretory Effect of TAK-438, a Novel Potassium-Competitive Acid Blocker, with Lansoprazole in Animals

Abstract

Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-Nmethylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI, to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases.

Second‑line triple therapy in failures with vonoprazan‑based triple therapy for eradication of Helicobacter pylori

“…Compared with LPZ, VPZ exhibits more potent and sustained acid-inhibitory effects, and induction of greater increases in gastric pH, consistent with the observation that VPZ accumulates to higher concentrations and is cleared at a slower rate from gastric glands (16,17). In addition, the intragastric pH following VPZ treatment (pH 5.2) has been identified to be significantly higher than that following esomeprazole treatment (pH 3.0) on day 1 of therapy (18).…”

Risk Factors for Delayed Ulcer Healing after Endoscopic Submucosal Dissection of Gastric Neoplasms

“…Vonoprazan is one of the new class of acid-suppressing agents that may be used as an alternative to PPIs as blocker of gastric hydrogen-potassium adenosine triphosphatase, which inhibits the critical final step in gastric acid secretion by reversing K+-competitive ionic binding. The pharmaceutical advantages of P-CAB over PPIs include more rapid, stronger and longer-lasting inhibition of gastric acid secretion after administration [7,15,16]. For the treatment of peptic ulcers, Miwa et al reported that a 20 mg dose of vonoprazan had a similar tolerability profile as a 30 mg dose of lansoprazole, and was not inferior to lansoprazole with respect to gastric ulcer healing [17].…”

Efficacy of a Potassium-Competitive Acid Blocker for Improving Symptoms in Patients with Reflux Esophagitis, Non-Erosive Reflux Disease, and Functional Dyspepsia

“…In comparison with PPIs, PCABs bind to the proton pump continuously in gastric parietal cells to reduce gastric acid secretion without requiring activation or being deactivated by the gastric acid. Furthermore, it was reported that PCABs are not affected by genetic polymorphisms of CYP2C19 (23,24). In patients with GERD whose gastric acid secretion was not suppressed sufficiently well by the administration of a PPI, it may be possible to control the secretion further by administering a PCAB.…”