Pantoprazole

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Abstract
Pantoprazole (Protonix® ) is an irreversible proton pump inhibitor (PPI) that reduces gastric acid secretion. In combination with two antimicrobial agents (most commonly metronidazole, clarithromycin or amoxicillin) for 6–14 days, pantoprazole 40mg twice daily produced Helicobacter pylori eradication rates of 71–93.8% (intent-to-treat [ITT] or modified ITT analysis) in patients without known antibacterial resistance. Pantoprazole-containing triple therapy was at least as effective as omeprazole- and similar in efficacy to lansoprazole-containing triple therapy in large trials. In the treatment of moderate to severe gastro-oesophageal reflux disease (GORD), oral pantoprazole 40 mg/day was as effective as other PPIs (omeprazole, omeprazole multiple unit pellet system, lansoprazole and esomeprazole) and significantly more effective than histamine H2-antagonists. Pantoprazole 20 mg/day provided effective mucosal healing in patients with GORD and mild oesophagitis. Intravenous pantoprazole 40 mg/day can be used in patients who are unable to take oral medication. Oral pantoprazole 20–40 mg/day for up to 24 months prevented relapse in most patients with healed GORD. According to preliminary data, oral pantoprazole 20 or 40 mg/day was effective t healing and preventing non-steroidal anti-inflammatory drug (NSAID)-relatedulcers, and intravenous pantoprazole was at least as effective as intravenous ranitidine in preventing ulcer rebleeding after endoscopic haemostasis. Oral or intravenous pantoprazole up to 240 mg/day maintained target acid output levels in most patients with hypersecretory conditions, including Zollinger-Ellison syndrome. Oral and intravenous pantoprazole appear to be well tolerated in patients with acid-related disorders in short- and long-term trials. Tolerability with oral pantoprazole was similar to that with other PPIs or histamine H2-antagonists in short-term trials. Formal drug interaction studies have not revealed any clinically significant interactions between pantoprazole and other agents. In conclusion, pantoprazole is an effective agent in the management of acid-related disorders. As a component of triple therapy for H. pylori eradication and as monotherapy for the healing of oesophagitis and maintenance of GORD, pantoprazole has shown similar efficacy to other PPIs and greater efficacy than histamine H2-antagonists. Limited data suggest that it is also effective in Zollinger-Ellison syndrome and in preventing ulcer rebleeding. Pantoprazole is well tolerated with minimal potential for drug interactions. The availability of pantoprazole as both oral and intravenous formulations provides flexibility when the oral route of administration is not appropriate. Thus, pantoprazole is a valuable alternative to other PPIs in the treatment of acid-related disorders. Pantoprazole, a substituted benzimidazole derivative, decreases gastric acid secretion by irreversibly inhibiting the proton pump (H+/K+-ATPase) in stimulated gastric parietal cells. Like other proton pump inhibitors (PPIs), pantoprazole is a prodrug which is activated and accumulates in an acid environment. However, pantoprazole is more stable in neutral to moderately acidic conditions in vitro than omeprazole, lansoprazole or rabeprazole, suggesting that it is less likely to become activated in moderately acidic compartments of the body. In addition, pantoprazole binds specifically in vitro to a region of the proton pump that is crucial for ATPase activity and acid transport; omeprazole, lansoprazole or rabeprazole have additional sites of binding. Optimal acid inhibition is observed after oral pantoprazole 40 mg/day administered in the morning. Acid inhibition with pantoprazole 40 mg/day is greater than that with ranitidine 300 mg/day or omeprazole 20 mg/day, similar to that with omeprazole 40 mg/day, greater than or similar to that with omeprazole multiple unit pellet system (MUPS) 20 mg/day and lower than or similar to that with lansoprazole 30 mg/day or esomeprazole 40 mg/day after repeated administration. Oral and intravenous pantoprazole 20 or 40mg once daily inhibit acid secretion to a similar extent. The suppression of acid output with intravenous pantoprazole 80mg was observed within 1 hour and continued for up to ≈21 hours. An intravenous bolus of pantoprazole 80mg, followed by an 8 mg/h infusion for 72 hours increased median intragastric pH to >6 after endoscopic haemostasis in patients with bleeding ulcer. Orally administered pantoprazole is rapidly absorbed and has an absolute oral bioavailability of 77%. Drug absorption is unaffected by the presence of food or antacids. Peak plasma concentrations and area under the plasma concentration-time curve (AUC) increased dose-dependently with intravenous pantoprazole 20–80mg. Pantoprazole is completely metabolised by the hepatic cytochrome P450 enzymes with no parent drug being found in the urine. The elimination half-life (t1/2) of pantoprazole is ≈1 hour. Most of the administered drug (≈80%) is excreted in urine as inactive metabolites. Dosage adjustments are not required in the elderly or in patients with renal impairment (including those undergoing regular haemodialysis). AUC and t1/2 are increased in patients with moderate to severe hepatic cirrhosis. Pantoprazole has not shown clinically significant drug interactions in formal studies. Oral pantoprazole 40mg twice daily in combination with two antimicrobial agents twice daily (most commonly metronidazole 400 or 500mg, clarithromycin 250 or 500mg or amoxicillin 1g) for 6–14 days eradicated Helicobacter pylori in 71–93.8% (intent-to-treat [ITT] or modified ITT analysis) of patients without any known antibacterial resistance. Triple therapy with pantoprazole 40mg once or twice daily for 5–10 days (ITT, 76.8–100%) was at least as effective as triple therapy containing omeprazole 40 mg/day (67.5–94.0%) and similar in efficacy to triple therapy containing lansoprazole 60 mg/day (73.1 and 80%) in the eradication of H. pylori in randomised trials in patients with peptic ulcer disease or nonulcer dyspepsia. Pantoprazole 20 or 40 mg/day was more effective than famotidine 40 mg/day, ranitidine 300 mg/day or nizatidine 150mg twice daily, and similar in efficacy to other PPIs (omeprazole 20 or 40 mg/day, omeprazole MUPS 40 mg/day, lansoprazole 30 mg/day or esomeprazole 40 mg/day) in the management of gastro-oesophageal reflux disease (GORD). Intravenous pantoprazole 40 mg/day was effective in the initial treatment of moderate to severe GORD; it may be used in patients who are unable to take oral medication and then switched to a similar dose of oral pantoprazole when oral intake is possible. Oral pantoprazole prevented relapse for at least 24 months in most patients with healed GORD. At 12 months, pantoprazole 20 and 40 mg/day were therapeutically equivalent in most trials; these dosages of pantoprazole were as effective as omeprazole 20 mg/day and more effective than ranitidine 150mg once or twice daily in the maintenance of healing. Pantoprazole 20 or 40mg was as effective as on-demand treatment in two studies in patients with GORD. After 12 weeks, the probability of remaining ulcer free was 72% with pantoprazole compared with 59% with placebo in patients receiving continued NSAID treatment. Preliminary data suggest that pantoprazole 20 or 40 mg/day has significantly greater efficacy than misoprostol 400 μ;g/day and similar efficacy to omeprazole 20 mg/day in the prevention of gastrointestinal lesions (including gastric and duodenal ulcers) in large, 6- or 12-month trials in patients receiving long-term continuous treatment with NSAIDs. Pantoprazole 40 mg/day was effective at healing NSAID-related peptic ulcers, with healing rates with pantoprazole being similar to those with omeprazole 20 mg/day or misoprostol 800 μ;g/day in a randomised trial. Limited data indicate that, in the prevention of ulcer rebleeding after endoscopic haemostasis, intravenous pantoprazole was at least as effective as intravenous ranitidine. High doses of pantoprazole achieved and maintained target acid output levels (H. pylori. In the US, oral pantoprazole is indicated for the initial and maintenance treatment of erosive oesophagitis associated with GORD, with 40 mg/day for up to 8 weeks (with an additional 8 weeks if required) being used for initial treatment and 40 mg/day being used for maintenance. In Europe, the intravenous formulation is recommended in those unable to use the oral formulation: the recommended dosage is 40 mg/day in those with duodenal or gastric ulcer or moderate to severe oesophagitis and 80 mg/day (adjusted based on gastric acid secretion) in those with Zollinger-Ellison syndrome or other pathological hypersecretory conditions. Intravenous pantoprazole is recommended in the US at dosages of 40 mg/day for 7–10 days in patients with GORD who are unable to use the oral formulation, and at dosages of 80mg every 12 hours (with adjustments if required based on acid output measurements) for the treatment of pathological hypersecretion associated with Zollinger-Ellison syndrome. The dosage of pantoprazole (either formulation) need not be adjusted in elderly patients or in patients with renal impairment. Dosage adjustments are not required in patients with mild to severe hepatic impairment in the US, whereas pantoprazole 20 mg/day or pantoprazole 40mg every other day is recommended in patients with hepatic cirrhosis in Europe.