What is the mechanism of action of vonoprazan (Potassium-Competitive Acid Blocker, P-CAB)?

Mechanism of Action of Vonoprazan (Potassium-Competitive Acid Blocker, P-CAB)

Vonoprazan suppresses gastric acid secretion through ionic, reversible binding to the gastric H+, K+-ATPase enzyme system (proton pump) in a potassium-competitive manner, blocking the final step of acid production without requiring activation by acid. 1

Key Pharmacological Properties

• Vonoprazan binds directly to the active proton pumps in a noncovalent and reversible manner, blocking access of K+ to the potassium-binding site of the pump 2, 1
• Unlike PPIs, vonoprazan is acid-stable and does not require conversion to an active form (not a prodrug), facilitating a more rapid onset of action 2, 3
• Vonoprazan selectively concentrates in the parietal cells in both resting and stimulated states, allowing it to inhibit acid secretion regardless of the secretory state 1, 4
• The binding affinity of vonoprazan to the H+, K+-ATPase is approximately 350 times higher than lansoprazole (a PPI), with a Ki value of 3.0 nmol/L 3, 4
• Vonoprazan has a high pKa of 9.37, which contributes to its accumulation in the acidic canaliculi of gastric parietal cells 3, 4

Pharmacodynamic Effects

• The onset of antisecretory effect occurs within 2-3 hours after a single dose, much faster than PPIs which typically require 3-5 days to reach maximal acid suppression 1, 5
• Vonoprazan maintains elevated intragastric pH levels for over 24 hours after a single dose 1, 6
• With 20 mg once daily dosing for 7 days, vonoprazan increases mean intragastric pH from 1.9 to 5.9 and maintains pH>4 for 85.2% of the time (approximately 20 hours per day) 1
• The inhibitory effect increases with repeated daily dosing, reaching steady state by Day 4 1
• After discontinuation, the antisecretory effect decreases but intragastric pH remains elevated compared to placebo for 24-48 hours 1

Pharmacokinetic Considerations

• Vonoprazan is absorbed rapidly, reaching maximum plasma concentration at 1.5-2.0 hours after oral administration 3
• Food has minimal effect on intestinal absorption, allowing for flexible administration timing unlike PPIs which require specific meal timing 2, 3
• The mean apparent terminal half-life is approximately 7.7 hours in healthy adults, longer than the 1-2 hour half-life of PPIs 2, 3
• Vonoprazan is metabolized mainly by CYP3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1 3
• Unlike PPIs, vonoprazan is minimally affected by CYP2C19 genetic polymorphisms, leading to less interindividual variability in therapeutic outcomes 2, 3

Clinical Implications of Mechanism

• The potent and prolonged acid suppression of vonoprazan results in higher serum gastrin concentrations compared to PPIs 2, 1
• Elevated gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels, which may cause false positive results in diagnostic investigations for neuroendocrine tumors 1
• The American Gastroenterological Association notes that vonoprazan should generally not be used as first-line therapy for acid-related conditions where clinical superiority has not been shown 2, 7
• The binding model of vonoprazan provides a template for design of novel potassium-competitive acid blockers 4

Safety Considerations Related to Mechanism

• Randomized trial data indicate vonoprazan is generally well-tolerated with short-term and medium-term safety profiles comparable to PPIs 2
• Due to its potent acid suppression, vonoprazan may be associated with similar infection risks as PPIs, including Clostridioides difficile infection 2
• Long-term safety data are more limited than for PPIs, though a 5-year study found similar adverse event profiles between vonoprazan and lansoprazole 2, 7
• Serum gastrin levels remain elevated during treatment with vonoprazan and return to normal within 4 weeks of discontinuation 1