What is Vonaprazone?

Vonoprazan: A Novel Potassium-Competitive Acid Blocker

Vonoprazan is a first-in-class potassium-competitive acid blocker (PCAB) that provides stronger and more consistent gastric acid suppression than traditional proton pump inhibitors (PPIs) for the treatment of acid-related disorders. 1

Mechanism of Action and Pharmacology

Vonoprazan works through a unique mechanism as a potassium-competitive acid blocker that:

• Inhibits the H+, K+-ATPase enzyme system in gastric parietal cells in a potassium-competitive manner 2
• Suppresses both basal and stimulated gastric acid secretion at the secretory surface of gastric parietal cells 2
• Does not require activation by acid (unlike PPIs) 2
• Selectively concentrates in parietal cells in both resting and stimulated states 2
• Binds to active pumps in a noncovalent and reversible manner 2

Key pharmacokinetic properties:

• Rapid onset of action (within 2-3 hours) 2
• Long-lasting effect with once-daily dosing 1
• Mean terminal half-life of approximately 7.7 hours 1
• Primarily metabolized by CYP3A4 with some involvement of CYP2B6, CYP2C19, CYP2D6, and SULT2A1 1
• Minimal effect of food on absorption 1

Clinical Applications

Vonoprazan is FDA-approved for:

1. Healing of erosive esophagitis: 20 mg once daily 1, 3
2. Maintenance of healed erosive esophagitis: 10 mg once daily 1, 3
3. Relief of heartburn in non-erosive GERD: 10 mg once daily 4
4. Treatment of H. pylori infection: 20 mg twice daily in combination with clarithromycin and amoxicillin 1

Clinical Efficacy

Vonoprazan demonstrates superior efficacy compared to PPIs:

• Erosive esophagitis healing: 92.9% healing rate with vonoprazan vs 84.6% with lansoprazole 3
• Maintenance of healing: Superior to lansoprazole in maintaining healed erosive esophagitis 3
• PPI-resistant GERD: Healing rates of 91.7% at 4 weeks and 88.5% at 8 weeks for PPI-resistant erosive esophagitis 5
• H. pylori eradication: Eradication rates >88% as both first-line and second-line therapy 6

Safety Profile

Vonoprazan is generally well tolerated with:

• Most common adverse events include abdominal pain, constipation, diarrhea, nausea, and dyspepsia 4
• Adverse reactions typically mild to moderate in severity 1
• No severe liver toxicity or neuroendocrine tumors reported in clinical studies 1

Drug Interactions

Important drug interactions to consider:

• CYP3A inhibition: Vonoprazan is a weak CYP3A inhibitor and may increase exposure of CYP3A4 substrates 2
• CYP2C19 inhibition: May reduce the active metabolite of clopidogrel and decrease platelet inhibition 2
• Drugs dependent on gastric pH: May alter absorption of antiretrovirals and other drugs requiring acidic environment for absorption 2
• Strong/moderate CYP3A4 inducers: May decrease vonoprazan exposure and reduce effectiveness 2

Special Populations

Dosage adjustments may be required in:

• Severe renal impairment (eGFR <30 mL/min): Dosage reduction recommended for erosive esophagitis treatment; not recommended for H. pylori treatment 2
• Moderate to severe hepatic impairment (Child-Pugh B/C): Dosage reduction recommended for erosive esophagitis treatment; not recommended for H. pylori treatment 2
• Elderly patients: No clinically meaningful differences in pharmacokinetics in patients ≥65 years of age 2

Advantages Over PPIs

• More potent acid suppression than PPIs 6
• Rapid onset of action 2
• No requirement for meal timing for optimal efficacy 4
• Effective in PPI-resistant GERD 6, 5
• More effective for severe (Los Angeles Grade C/D) esophagitis 3

Vonoprazan represents a significant advancement in the treatment of acid-related disorders with its unique mechanism of action and superior acid suppression compared to traditional PPIs, particularly for patients with more severe disease or those who have inadequate response to PPI therapy.