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Uncover the evolution of gastric acid suppression beyond proton pump inhibitors at Asian Pain Academy. Explore the latest advancements in treatment efficacy.
Gastric Acid Suppression Beyond Proton Pump Inhibitors
Gastric acid suppression has evolved significantly over the decades, with each phase marked by advancements in understanding and treatment efficacy. Initially, antacids were the mainstay for managing acid-related disorders, offering symptomatic relief through the neutralisation of gastric acid. This was followed by the introduction of H2 antagonists, which provided more targeted inhibition of histamine-induced acid secretion. The advent of proton pump inhibitors (PPIs) in the late 20th century represented a paradigm shift, offering profound and sustained acid suppression by irreversibly binding to the H+/K+ ATPase enzyme.
Despite the success of PPIs, their limitations, including delayed onset of action and incomplete acid suppression in some patients, necessitated further innovation. The most recent development in this therapeutic area is vonoprazan, a potassium-competitive acid blocker (P-CAB). Vonoprazan offers a novel mechanism of action, characterized by rapid and potent acid suppression, thus addressing some of the shortcomings associated with traditional PPIs. This article will explore the historical progression of gastric acid suppression therapies, emphasizing the clinical implications and comparative efficacy of these evolving pharmacological interventions.
Potassium-Competitive Acid Blockers (P-CABs): What They Are and How They Work
What is Potassium-Competitive Acid Blockers (P-CABs)?
Potassium-competitive acid blockers (P-CABs) represent a novel class of pharmacological agents designed to suppress gastric acid secretion. The concept of P-CABs emerged in the 1980s with the development of SCH28080, an imidazopyridine compound that marked the initial step towards competitive inhibition of the H+, K+-ATPase enzyme at the potassium binding site. Although SCH28080 showed potential, its development was discontinued due to concerns over hepatic toxicity.
Subsequent research focused on refining the chemical structure of SCH28080, leading to the creation of several derivatives with improved safety profiles and efficacy. This exploration culminated in the development of various compounds, such as linaprazan, soraprazan, and vonoprazan, each with distinct chemical backbones ranging from imidazopyridine to pyrrole derivatives. Among these, vonoprazan has emerged as a clinically significant P-CAB, being introduced in Japan in 2015 and later gaining approval in China in 2019 for the treatment of gastric and duodenal ulcers, reflux esophagitis, and for the prevention of ulcers associated with low-dose aspirin or NSAID use.
How Do Potassium-Competitive Acid Blockers Work?
P-CABs function as weak bases that inhibit gastric acid secretion by targeting the H+, K+-ATPase enzyme, commonly known as the gastric proton pump, in the parietal cells of the stomach. This enzyme is responsible for the final step in the production of gastric acid, making it a critical target for acid suppression therapies.
The primary mechanism of P-CABs involves competitive inhibition at the potassium binding site of the H+, K+-ATPase enzyme. Unlike proton pump inhibitors (PPIs), which require activation in acidic conditions to inhibit the proton pump, P-CABs bind directly to the enzyme without needing acid activation. This direct binding results in a rapid onset of action and provides reversible inhibition of acid secretion.
A key factor in the efficacy of P-CABs is their pKa value, which influences their ability to be protonated and subsequently inhibit the acid pump. Vonoprazan, for example, has a high pKa of 9.3, allowing it to remain in a protonated state effectively and exert strong inhibition on the acid pump. This property enables P-CABs to provide better control over gastric acid secretion compared to PPIs.
To maintain their inhibitory effect, P-CABs require a consistent plasma concentration, which can potentially extend their duration of action. This consistent plasma presence ensures sustained inhibition of gastric acid production, making P-CABs a promising alternative to traditional acid suppression therapies.
What is Vonoprazan?
Vonoprazan fumarate is a modern potassium-competitive acid blocker (P-CAB) specifically designed to inhibit gastric acid secretion with a unique and potent mechanism of action. Chemically, it is described as 1H-pyrrole-3-methanamine, 5-(2-fluorophenyl)-N-methyl-1-(3-pyridinylsulfonyl)-, in its fumarate form. Its empirical formula is C17H16FN3O2S•C4H4O4, and it has a molecular weight of 461.5. The substance appears as a white to nearly white crystalline powder and is soluble in dimethyl sulfoxide while showing varying solubilities in other organic solvents and water. It is practically insoluble in 2-propanol, acetone, 1-octanol, and acetonitrile.
Vonoprazan tablets are formulated for oral administration, available in 10 mg and 20 mg dosages. The tablet composition includes excipients such as ascorbic acid, croscarmellose sodium, ferric oxides, and fumaric acid, which are incorporated to enhance the drug's stability and efficacy in delivering the medication.
Vonoprazan - Mechanism of Action
Vonoprazan operates by binding to the H+, K+-ATPase enzyme in the parietal cells of the stomach, preventing the enzyme's interaction with potassium ions. Here’s a step-by-step breakdown of its action:
Reaching the Gastric Lumen: Once ingested, vonoprazan reaches the gastric lumen where it exerts its effect.
Binding to the Enzyme: It specifically binds to the E2 form of the H+, K+-ATPase enzyme.
Preventing Potassium Binding: Vonoprazan prevents potassium ions from binding to the enzyme.
Inhibiting Dephosphorylation: It inhibits the potassium-dependent dephosphorylation of the enzyme.
Preventing Conformational Change: By doing so, it prevents the enzyme from undergoing its conformational change from the E2 to the E1 form.
Reversible Inhibition: This action leads to the reversible inhibition of the H+, K+-ATPase enzyme.
Inhibiting Acid Secretion: Ultimately, vonoprazan effectively inhibits gastric acid secretion.
This mechanism allows vonoprazan to provide rapid and sustained acid suppression, addressing some of the limitations associated with traditional proton pump inhibitors (PPIs) and offering an advanced therapeutic option for acid-related diseases.
Pharmacokinetics of Vonoprazan
Absorption
Vonoprazan reaches steady-state concentrations by days 3-4 of administration, and its pharmacokinetic profile remains consistent over time. It exhibits dose-proportional increases in the maximum concentration (Cmax) and the area under the plasma concentration-time curve (AUC) across dosages ranging from 10 to 40 mg. The drug shows minimal accumulation, with an accumulation index of less than 1.2, indicating efficient clearance with repeated dosing. When administered with a high-fat meal, vonoprazan's absorption is slightly affected, resulting in a 5% increase in Cmax and a 15% increase in AUC, accompanied by a 2-hour delay in the median time to reach maximum concentration (Tmax). These changes are not considered clinically significant, ensuring reliable efficacy regardless of food intake.
Distribution
Vonoprazan demonstrates 85-88% plasma protein binding across a concentration range of 0.1 to 10 mcg/mL. This high level of plasma protein binding is concentration-independent, indicating that vonoprazan maintains consistent distribution within the body irrespective of the dose administered.
Metabolism
Vonoprazan is metabolized into inactive derivatives through multiple pathways involving cytochrome P450 enzymes, including CYP3A4/5, CYP2B6, CYP2C19, CYP2C9, and CYP2D6, as well as through conjugation reactions. The pharmacokinetic profiles of vonoprazan do not show significant differences based on CYP2C19 metabolizer status, suggesting that genetic polymorphisms have minimal impact on its metabolism. This consistency in metabolism contributes to its predictable and stable pharmacokinetic behavior.
Excretion
After oral administration of radio-labeled vonoprazan, approximately 67% of the dose is excreted in urine, with 8% of it as unchanged drug. Additionally, 31% of the dose is excreted in feces, with 1.4% as unchanged drug. This balanced elimination route through both renal and fecal pathways ensures comprehensive clearance of vonoprazan from the body.
Stability and Absorption
Vonoprazan’s high acid dissociation constant (pKa) of 9.37 allows for rapid absorption and stability under acidic conditions. This stability facilitates the drug's accumulation in acid-secreting canaliculi, leading to effective inhibition of the H+/K+-ATPase enzyme and consistent acid-suppressive effects. This property ensures that vonoprazan remains effective even in the highly acidic environment of the stomach.
Dissociation and Half-Life
Vonoprazan exhibits a slow dissociation rate from the proton pump, which, along with the minimal influence of CYP2C19 polymorphisms, ensures prolonged efficacy. It has a mean elimination half-life of up to 9 hours, allowing for sustained acid suppression beyond that offered by conventional proton pump inhibitors (PPIs).
Pharmacokinetic Advantages Over PPIs
The pharmacokinetic properties of vonoprazan, including its stable binding to the proton pump, rapid onset of action, and consistent efficacy regardless of CYP2C19 polymorphism status, provide significant advantages over PPIs. Clinical evidence supports the superior efficacy of vonoprazan in treating and maintaining the healing of erosive esophagitis and providing relief for patients with PPI-resistant gastroesophageal reflux disease (GERD). Its ability to offer more effective and sustained acid suppression makes it a favorable treatment option for acid-related gastrointestinal disorders.
Advantages of Vonoprazan, a potassium-competitive acid blocker (P-CAB) over proton pump inhibitors (PPIs)
Vonoprazan, a potassium-competitive acid blocker (P-CAB), has several advantages over proton pump inhibitors (PPIs) based on the provided data:
Proton Pump Activation:
Vonoprazan: Proton pump activation is not necessary, leading to more consistent acid suppression.
PPIs: Require proton pump activation, which can be variable and less reliable.
24-Hour Intragastric pH > 4:
Vonoprazan: Maintains intragastric pH > 4 for a significantly higher percentage of time (82.9 - 85.9%).
PPIs: Only maintain this pH level for 46 - 58% of the time.
Night-time Acid Suppression:
Vonoprazan: Provides superior acid suppression at night, with pH > 4 for 67.9 ± 28.3% of the time.
PPIs: Less effective at night, with much lower percentages (12.9 ± 10.9 for ESO and 15.3 - 13.3 for R).
Influence of Meal:
Vonoprazan: No influence from meals, maintaining its efficacy regardless of food intake.
PPIs: Reduced effect after meals, leading to potential variations in effectiveness.
Short-term Side Effects:
Vonoprazan: Generally limited to diarrhoea, constipation, eczema, and upper respiratory tract inflammation in less than 5% of cases.
PPIs: Broader range of side effects including headache, rash, dizziness, constipation, diarrhoea, flatulence, and abdominal pain.
Long-term Side Effects:
Vonoprazan: Long-term side effects are still under investigation.
PPIs: Known long-term side effects include fundic polyps, vitamin B12 and micronutrient deficiencies, liver disease, hypomagnesemia, and kidney disease.
Approved Indications of Vonoprazan
Vonoprazan is a potassium-competitive acid blocker (P-CAB) that has been approved for several indications related to gastric acid suppression and management of acid-related disorders. Its clinical applications span a variety of conditions, including eradication of Helicobacter pylori and the prevention and treatment of gastric and duodenal ulcers. Below are the approved indications for vonoprazan:
1. Adjunct to Helicobacter pylori Eradication
Vonoprazan is used as an adjunct therapy for the eradication of Helicobacter pylori in conditions such as:
Gastric ulcer
Duodenal ulcer
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma
Idiopathic thrombocytopenic purpura
Post-endoscopic resection of early-stage gastric cancer
Helicobacter pylori-associated gastritis
2. Prevention of Recurrence of Gastric or Duodenal Ulcers
Vonoprazan is effective in preventing the recurrence of gastric or duodenal ulcers in patients undergoing:
Nonsteroidal anti-inflammatory drugs (NSAIDs) administration
Low-dose aspirin administration
3. Treatment of Reflux Esophagitis
Vonoprazan is approved for the treatment of reflux esophagitis, providing rapid and sustained acid suppression to alleviate symptoms and promote healing of the esophageal mucosa.
4. Treatment of Gastric Ulcer
Vonoprazan is indicated for the treatment of gastric ulcers, helping to reduce gastric acid secretion, thereby allowing the ulcer to heal and preventing further damage to the gastric lining.
5. Treatment of Duodenal Ulcer
Vonoprazan is also approved for the treatment of duodenal ulcers, effectively suppressing gastric acid production and facilitating the healing of the ulcerated tissue in the duodenum.
Dosage and Administration of Vonoprazan
Reflux Esophagitis (Erosive Esophagitis)
Usual Dose: 20 mg of vonoprazan once daily.
Duration: Treatment should be limited to 4 weeks. If the therapeutic effect is insufficient, treatment may be extended up to 8 weeks.
Gastric Ulcer
Usual Dose: 20 mg of vonoprazan once daily.
Duration: Administration should be limited to 8 weeks.
Duodenal Ulcer
Usual Dose: 20 mg of vonoprazan once daily.
Duration: Administration should be limited to 6 weeks.
Prevention of Recurrence of Gastric or Duodenal Ulcer During Low-Dose Aspirin Administration
Usual Dose: 10 mg of vonoprazan once daily.
Adjunct to Helicobacter pylori Eradication
First-line Treatment:
Dosage: The following three drugs are administered orally at the same time twice daily for 7 days:
20 mg vonoprazan
750 mg amoxicillin hydrate
200 mg clarithromycin (the dose of clarithromycin may be increased as required, up to a maximum of 400 mg twice daily as per physician judgment)
Second-line Treatment (After Failure of First-line Therapy):
Dosage: The following three drugs are administered orally at the same time twice daily for 7 days:
20 mg vonoprazan
750 mg amoxicillin hydrate
250 mg metronidazole (antibiotic doses should follow respective label recommendations for H. pylori eradication)
General Administration Guidance
Consistency: Vonoprazan should be taken consistently according to the prescribed dosage and duration to ensure optimal efficacy and minimize the risk of adverse effects.
Meal Considerations: Although a high-fat meal can slightly affect vonoprazan absorption, these changes are not clinically significant, and vonoprazan can be taken with or without food.
Adherence: Patients should adhere strictly to the prescribed treatment regimen, particularly in combination therapies for H. pylori eradication, to ensure successful outcomes.
Adverse Effects of Vonoprazan
Vonoprazan is a potassium-competitive acid blocker (P-CAB) used to treat conditions like gastroesophageal reflux disease (GERD) and peptic ulcer disease. While it is generally well-tolerated, some potential adverse effects associated with vonoprazan include:
Common Adverse Effects:
Diarrhea: Some patients may experience loose stools or diarrhea.
Constipation: Opposite to diarrhea, some may suffer from constipation.
Nausea: A feeling of sickness or an urge to vomit can occur.
Headache: Some users report headaches during treatment.
Abdominal Pain: Discomfort or pain in the stomach area may be experienced.
Less Common Adverse Effects:
Gastrointestinal Issues: Including dyspepsia (indigestion), flatulence (gas), and gastritis.
Dizziness: Some patients might feel dizzy or lightheaded.
Liver Enzyme Abnormalities: There may be changes in liver function tests indicating hepatic involvement.
Upper Respiratory Tract Infections: A slight increase in the risk of infections like the common cold.
Rare but Serious Adverse Effects:
Hypomagnesemia: Long-term use may lead to low levels of magnesium in the blood, which can result in muscle spasms, arrhythmias, or seizures.
Vitamin B12 Deficiency: Prolonged treatment might impair vitamin B12 absorption, leading to deficiency.
Clostridium difficile Infection: An increased risk of gastrointestinal infections, particularly Clostridium difficile-associated diarrhea.
Allergic Reactions:
Hypersensitivity Reactions: Some patients may experience allergic reactions like rash, itching, or even anaphylaxis in rare cases.
Regulatory Approval Status of Vonoprazan
Japan:
Vonoprazan was first approved in Japan in February 2015. It is widely used for the treatment of acid-related disorders such as gastroesophageal reflux disease (GERD) and Helicobacter pylori infection (Phathom Pharmaceuticals, Inc.) (Phathom Pharmaceuticals, Inc.).
United States:
Vonoprazan has been approved by the FDA for multiple indications, including:
Treatment of erosive esophagitis (Erosive GERD) and relief of associated heartburn.
Maintenance of healing of erosive esophagitis.
Relief of heartburn associated with non-erosive GERD.
Treatment of Helicobacter pylori infection in combination with antibiotics like amoxicillin and clarithromycin (Phathom Pharmaceuticals, Inc.) (Drugs.com).
India:
Vonoprazan has been approved by the Drug Controller General of India (DCGI) for the treatment of reflux esophagitis and other acid peptic disorders. It is marketed in India through non-exclusive licensing agreements with pharmaceutical companies (Cipla) (PharmaTutor).
Other Countries:
Vonoprazan is approved and marketed in several other countries across Asia and Latin America by Takeda Pharmaceuticals (Phathom Pharmaceuticals, Inc.) (Phathom Pharmaceuticals, Inc.).
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