What is P-CAB (Potassium-Competitive Acid Blocker)?

What is P-CAB (Potassium-Competitive Acid Blocker)?

P-CABs are a novel class of gastric acid suppressants that directly and reversibly block the potassium-binding site of the H+/K+-ATPase proton pump, offering more rapid, potent, and sustained acid inhibition compared to traditional proton pump inhibitors (PPIs). 1

Mechanism of Action

P-CABs work fundamentally differently from PPIs:

• Direct competitive inhibition: P-CABs competitively block the potassium-binding site of the proton pump through reversible ionic binding, preventing potassium from accessing the pump 1
• No prodrug activation required: Unlike PPIs, P-CABs do not require acid activation and are not prodrugs, allowing immediate pharmacologic effect 1, 2
• Acid-stable formulation: P-CABs remain stable in acidic environments, eliminating the need for enteric coating 1

Key Pharmacologic Advantages Over PPIs

Rapid onset of action: P-CABs achieve antisecretory effect within 2-3 hours of the first dose, reaching maximal acid suppression within 1 day compared to 3-5 days for PPIs 1, 2

Extended duration:

• Half-life of 6-9 hours versus 1-2 hours for PPIs 1
• Maintain target intragastric pH >4 for up to 85% of a 24-hour period (20 hours) at therapeutic doses 2
• Provide superior nighttime acid control 1

Consistent efficacy across populations: P-CABs are not metabolized by CYP2C19, eliminating the genetic variability that affects PPI metabolism and therapeutic response 1, 3

Flexible dosing: Can be taken with or without food at any time of day, unlike PPIs which require administration 30-60 minutes before meals 1

Available P-CAB Agents

Examples include vonoprazan, tegoprazan, revaprazan, fexuprazan, linaprazan, zastaprazan, and keverprazan 1

Vonoprazan is the most extensively studied and is FDA-approved in the United States for 2:

• Healing of all grades of erosive esophagitis
• Maintenance of healed erosive esophagitis
• Relief of heartburn in non-erosive GERD
• Treatment of H. pylori infection (in combination with antibiotics)

Current Clinical Role Per AGA Guidelines (2024)

Where P-CABs SHOULD be used 1:

• Severe erosive esophagitis (Los Angeles grade C/D) that has failed twice-daily PPI therapy
• H. pylori eradication regimens (may replace PPIs for most patients)

Where P-CABs MAY be considered 1:

• Selected patients with documented acid-related reflux failing twice-daily PPIs
• Potential utility in on-demand therapy for heartburn (pending more data)
• Potential utility in bleeding peptic ulcers with high-risk stigmata (pending more data)

Where P-CABs should generally NOT be used as first-line 1:

• Uninvestigated heartburn or non-erosive GERD
• Mild erosive esophagitis (LA grade A/B)
• Routine peptic ulcer disease treatment or prophylaxis
• Any acid-related condition where clinical superiority over PPIs has not been demonstrated

Safety Considerations

Shared risks with PPIs: Both classes carry similar concerns related to profound acid suppression, including increased risk of enteric infections and C. difficile 1, 3

Hypergastrinemia: P-CABs elevate serum gastrin levels higher than PPIs, though levels return toward baseline within weeks after discontinuation 1, 3, 2

Limited long-term data: While short-term and medium-term safety profiles are comparable to PPIs, extensive long-term safety data is still accumulating 1, 3

Drug interactions: Vonoprazan is contraindicated with rilpivirine-containing products per FDA labeling 3, 2

Critical Practical Limitations

Cost barrier: P-CABs are significantly more expensive than generic PPIs, which limits accessibility and may not be cost-effective even when modestly clinically superior 1

Insurance authorization: Greater obstacles exist in obtaining payor coverage compared to PPIs 1

Dosage adjustments needed: Vonoprazan requires dose reduction in severe renal impairment (eGFR <30 mL/min) and moderate-to-severe hepatic impairment (Child-Pugh B/C) for certain indications 2

Common Pitfall to Avoid

Do not use P-CABs as routine first-line therapy simply because they are "newer" or theoretically superior—the AGA explicitly recommends against this approach based on cost, access barriers, and lack of demonstrated clinical superiority in most acid-related conditions 1. Reserve P-CABs for patients with severe disease or documented PPI failure where their pharmacologic advantages translate into meaningful clinical benefit.