P-CAB

Potassium-competitive acid blockers (PCABs) (P-CABs)

• have been discovered as a possible acid suppression therapeutic option
• at the enzyme level PCABs compete with K+ to suppress acid formation (1)
  • are weak bases, and the protonated form of these drugs inhibits the H+ K+ ATPase enzyme (2)
  • when PCAB binds to the enzyme, it stops K+ from attaching and activating
    • action of gastric H+/K+-ATPase in the apical membrane of parietal cells promotes a very high concentration of H+ in the lumen compared to plasma
      • potassium ion plays an essential role in activating gastric H+/K+-ATPase and is required for the enzyme to function
      • PCABs do not require proton pump activation to achieve their action; further, they have rapid action onset and reduce acid secretion due to a steady rise in their plasma concentration (2)
        • at rest, H+/K+-ATPase is confined to tubulovesicular regions of a parietal cell with low K+ concentrations and membranes that are impermeable to K+ - in this state, the enzyme is incapable of activating and transporting H+ ions
        • when the parietal cell is stimulated, the tubulovesicular components merge with the cell’s apical membrane
        • after being exposed to K+-containing luminal fluid, the H+/K+-ATPase enzyme can begin to exchange H+ for K
    • PCABs are extremely selective for gastric H+, K+-ATPase - thus restricting stomach acid production while acting quickly (1)

In an analysis (24 studies), efficacy of vonoprazan ranked best at initial healing phase vs other PPIs, with moderate safety, & 20mg/d an efficacious starting dose (3)

• in maintained healing of grade C/D esophagitis, standard dose vonoprazan and lansoprazole ranked first in efficacy
• studies included 3 potassium competitive acid blockers (vonoprazan, tegoprazan, and keverprazan) and 6 PPIs (lansoprazole, esomeprazole, omeprazole, rabeprazole extended-release (ER), pantoprazole, and dexlansoprazole)

Comparative Efficacy of P-CAB vs Proton Pump Inhibitors for erosive esophagitis (EE) (4):

• studies with patients both with and without severe EE at the beginning, Keverprazan 20mg qd was ranked as the most effective treatment with a healing rate of 84.7, followed by Ilaprazole 10mg qd with a healing rate of 82.0 at 8 weeks
• subgroup analysis showed that most P-CABs had higher healing rates than PPIs, especially for patients with severe EE

Reference:

1. Leowattana W, Leowattana T. Potassium-competitive acid blockers and gastroesophageal reflux disease. World J Gastroenterol. 2022 Jul 28;28(28):3608-3619.
2. 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 Dec 13;9(7):63-68.
3. Zhuang Q et al. Comparative Efficacy of P-CAB vs Proton Pump Inhibitors for Grade C/D Esophagitis: A Systematic Review and Network Meta-analysis. The American Journal of Gastroenterology ():10.14309/ajg.0000000000002714, March 22, 2024. | DOI: 10.14309/ajg.0000000000002714
4. Liu Y, Gao Z, Hou X. Potassium-competitive acid blockers and proton-pump inhibitors for healing of erosive esophagitis: a systematic review and network meta-analysis. Therapeutic Advances in Gastroenterology. 2024;17.