Pantoprazole

A Review of its Pharmacological Properties and Therapeutic Use in Acid-Related Disorders

Abstract

Synopsis

Pantoprazole is an irreversible proton pump inhibitor which, at the therapeutic dose of 40mg, effectively reduces gastric acid secretion.

In controlled clinical trials, pantoprazole (40mg once daily) has proved superior to ranitidine (300mg once daily or 150mg twice daily) and equivalent to omeprazole (20mg once daily) in the short term (≤8 weeks) treatment of acute peptic ulcer and reflux oesophagitis. Gastric and duodenal ulcer healing proceeded significantly faster with pantoprazole than with ranitidine, and at similar rates with pantoprazole and omeprazole. The time course of gastric ulcer pain relief was similar with pantoprazole, ranitidine and omeprazole, whereas duodenal ulcer pain was alleviated more rapidly with pantoprazole than ranitidine. Pantoprazole (40mg once daily) showed superior efficacy to famotidine (40mg once daily) in ulcer healing and pain relief after 2 weeks in patients with duodenal ulcer in a large multicentre nonblinded study.

In mild to moderate acute reflux oesophagitis, significantly greater healing was obtained with pantoprazole than with ranitidine and famotidine, whereas similar healing rates were seen with pantoprazole and omeprazole. Pantoprazole showed a significant advantage over ranitidine in relieving symptoms of heartburn and acid regurgitation. Reflux symptoms were similarly alleviated by pantoprazole and omeprazole.

Preliminary results indicate that triple therapy with pantoprazole, clarithromycin and either metronidazole or imidazole is effective in the treatment of Helicobacter pylori-associated disease; however, these findings require confirmation in large well-controlled studies.

Pantoprazole appears to be well tolerated during short term oral administration, with diarrhoea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%) and skin rash (0.4%) representing the most frequent adverse events. The drug has lower affinity than omeprazole or lansoprazole for hepatic cytochrome P450 and shows no clinically relevant pharmacokinetic or pharmacodynamic interactions at therapeutic doses with a wide range of drug substrates for this isoenzyme system.

In conclusion, pantoprazole is superior to ranitidine and as effective as omeprazole in the short term treatment of peptic ulcer and reflux oesophagitis, has shown efficacy when combined with antibacterial agents in H. pylori eradication, is apparently well tolerated and offers the potential advantage of minimal risk of drug interaction.

Pharmacodynamic Properties

Pantoprazole causes irreversible inhibition of proton pump (H+, K+-ATPase) function. It is chemically more stable than omeprazole or lansoprazole under neutral to mildly acidic conditions, but is rapidly activated under strongly acidic conditions. This pH-dependent activation profile underlies the improved in vitro selectivity of pantoprazole against parietal H+, K+-ATPase compared with omeprazole.

Oral pantoprazole (20 to 60mg once daily for 5 to 7 days) produces dose-related inhibition of basal, nocturnal and 24-hour gastric acid secretion in healthy volunteers, with minimal additional inhibition at higher doses (80 and 120mg). An intragastric pH >3 was sustained for 8 and 14 hours with pantoprazole 40 and 60mg, respectively, in healthy volunteers. Steady-state gastric acid inhibition was significantly more pronounced when pantoprazole (40mg) was given in the morning rather than the evening. In patients with duodenal ulcer and Helicobacter pylori infection, an intragastric pH >3 was sustained for 19 hours with pantoprazole 40mg.

Oral pantoprazole 40mg appears to be more effective than omeprazole 20mg and as effective as omeprazole 40mg in inhibiting gastric acid secretion in healthy volunteers. Once daily administration of pantoprazole 40mg to healthy volunteers was significantly more effective than omeprazole 20mg in elevating daytime and 24-hour intragastric pH, and marginally more effective than omeprazole 40mg in inhibiting nocturnal acid secretion. Pantoprazole was significantly superior to ranitidine 300mg once daily in increasing median daytime and 24-hour intragastric pH.

Pentagastrin-stimulated acid secretion in healthy volunteers is inhibited in a potent and long-lasting (> 24hours) manner after oral (20 to 40mg once daily) or intravenous (≤80mg single dose; 15 to 30mg once daily) administration of pantoprazole.

In patients with peptic ulcer, a marginally greater elevation in median fasting serum gastrin level was seen after 2 to 4 weeks’ treatment with pantoprazole 40mg once daily (<60%) than with ranitidine 300mg once daily (≈30%), whereas similar increases (≤40%) were seen with pantoprazole 40mg and omeprazole 20mg (both once daily).

Serum pepsinogen I levels are elevated following oral pantoprazole administration, the effect being more exaggerated in patients with H. pylori infection (≤ 150% increase).

Toxicity studies in mice have shown gastric mucosal and submucosal glandular hyperplasia, but no evidence of gastric tumours, on prolonged exposure to high dose pantoprazole. In humans, long term (36 months) therapy with pantoprazole (40 to 80mg daily) has not been associated with any significant increase in enterochromaffin-like cell density.

Pantoprazole does not appear to influence endocrine function on short term administration. No significant changes in adrenocorticotrophic hormone (ACTH)-stimulated plasma testosterone or Cortisol levels, or basal plasma thyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin or somatotrophic hormone levels were observed.

Pharmacokinetic Properties

Pantoprazole is rapidly absorbed after oral administration, with peak plasma concentrations of 1.1 to 3.1 mg/L occurring 2 to 4 hours after ingestion of an enteric-coated 40mg tablet. The drug is subject to low first-pass hepatic extraction, displaying an estimated absolute oral bioavailability of 77%. Concomitant food intake does not affect bioavailability. Pantoprazole has a short mean plasma terminal elimination half-life (t1/2β; 0.9 to 1.9 hours); however, inhibition of acid secretion, once accomplished, persists long after the drug has been cleared from the circulation. On repeated oral administration, the pharmacokinetics of pantoprazole (20 and 40 mg once daily) are similar to those after single dose administration.

In accordance with its high degree of plasma protein binding (≈ 98%), Pantoprazole undergoes extensive hepatic metabolism via cytochrome P450-mediated oxidation followed by sulphate conjugation. Elimination is predominantly renal, with -80% of an oral or intravenous dose being excreted as urinary metabolites; the remainder is excreted in the faeces and originates primarily from biliary secretion.

The pharmacokinetics of pantoprazole do not appear to be modified to any clinically relevant extent by renal impairment or haemodialysis. Although metabolism and elimination of pantoprazole are impaired in patients with hepatic dysfunction, Cmax is only marginally elevated, indicating that pantoprazole may be administered to patients with hepatic impairment without dosage adjustment. In the elderly, the pharmacokinetics of pantoprazole are comparable to those in the young.

Pantoprazole has lower affinity than omeprazole or lansoprazole for the hepatic cytochrome P450 (CYP) enzyme system and does not appear to induce CYP activity. In healthy human volunteers, pantoprazole shows no clinically relevant interaction at therapeutic doses with phenazone (antipyrine), diazepam, digoxin, theophylline, carbamazapine, diclofenac, phenprocoumon, phenytoin, warfarin, nifedipine, caffeine, metoprolol or ethanol. In addition, it does not appear to compromise hormonal contraceptive efficacy as no interaction with a low dose combined oral contraceptive was shown. Conversely, the pharmacokinetics of pantoprazole are not modified to any clinically relevant extent by coadministered antacids, phenazone, phenytoin, digoxin or theophylline.

Therapeutic Use

In clinical trials investigating the efficacy of pantoprazole therapy in patients with peptic ulcer or reflux oesophagitis, pantoprazole (40mg), omeprazole (20mg) and famotidine (40mg) were administered once daily, and ranitidine (300mg) was administered as a single daily dose (peptic ulcer) or in 2 divided doses (reflux oesophagitis).

Healing of acute gastric ulcer proceeded significantly faster with pantoprazole than with ranitidine [cumulative ulcer healing rates after 2, 4 and 8 weeks’ treatment of 37, 87 and 97% (pantoprazole) and 19, 58 and 80% (ranitidine)]. However, pain relief was similar with the 2 treatments (72% of pantoprazole and 68% of ranitidine recipients were completely pain-free after 2 weeks).

In comparison with omeprazole, the gastric ulcer healing rate was initially (after 4 weeks) significantly higher with pantoprazole (88 vs 77%); however, after 8 weeks, cumulative ulcer healing rates with the 2 drugs were similar (97 vs 96%). Both drugs rapidly alleviated gastric pain (79% of pantoprazole and 68% of omeprazole recipients were pain-free after 2 weeks), nausea, vomiting, retching, heartburn and acid regurgitation.

Pantoprazole has performed significantly better than ranitidine in healing uncomplicated acute duodenal ulcer and in alleviating ulcer pain. Ulcer healing rates were invariably higher with pantoprazole than with ranitidine (61 to 81% vs 35 to 53% at 2 weeks; 82 to 100% vs 70 to 86% at 4 weeks). This advantage generally translated into a significant superiority for pantoprazole in relief of ulcer pain (77 to 84% vs 58 to 72% of patients pain-free) and other gastrointestinal symptoms (79 to 87 vs 64 to 71 % of patients symptom-free) after 2 weeks’ therapy. pantoprazole has a relatively low apparent volume of distribution (mean 0.16 L/kg at steady-state). Following an initial distribution phase, plasma pantoprazole concentrations decline in a monophasic manner, with an apparent mean t1/2β of 0.9 to 1.9 hours.

Pantoprazole achieved duodenal ulcer healing and pain relief in a significantly larger proportion of patients than did famotidine after 2 weeks (ulcer healing 82 vs 68%; pain relief 87 vs 72%); however, ulcer healing rates were similar in the 2 treatment groups after 4 weeks’ treatment (93 vs 88%).

In contrast, pantoprazole and omeprazole have quantitatively similar effects on duodenal ulcer healing and symptoms. Cumulative ulcer healing rates were similar with the 2 drugs (65 to 74% at 2 weeks; 89 to 96% at 4 weeks), as was relief from ulcer pain (81 to 86% pain-free at 2 weeks).

Recent findings indicate that pantoprazole is effective in the treatment of peptic ulcers poorly responsive to standard or high dosages of histamine H2 receptor antagonists. A healing rate of 96.7% was achieved in patients with ulcers refractory to high dose ranitidine following 2 to 8 weeks’ treatment with pantoprazole 40 to 80 mg/day, and pantoprazole maintenance therapy was effective in preventing ulcer recurrence for up to 3 years.

In the treatment of mild to moderate acute reflux oesophagitis, pantoprazole appears to be of equivalent efficacy to standard dose omeprazole but superior to standard dose ranitidine or famotidine. Significantly higher healing rates were obtained with pantoprazole compared to ranitidine (69 vs 57% at 4 weeks; 82 vs 67% at 8 weeks) and famotidine (80 vs 57% at 4 weeks; 93 vs 72% at 8 weeks). Marked symptomatic improvement occurred with pantoprazole and ranitidine as early as week 2 of treatment, with pantoprazole showing a significant advantage in relieving heartburn (weeks 2 and 4) and acid regurgitation (week 4). Overall relief of the 3 main symptoms of reflux (heartburn, acid regurgitation and odynophagia) significantly favoured pantoprazole over ranitidine (72 vs 52% of patients with complete resolution at 4 weeks).

Pantoprazole and omeprazole were equally effective in the endoscopic healing and symptomatic relief of reflux oesophagitis, as reflected in similar ulcer healing rates (74 to 79% vs 75 to 79% at 4 weeks; 90 to 94% vs 91 to 94% at 8 weeks), and rates of resolution of reflux symptoms (59 to 71% vs 69 to 73% at 2 weeks; 83 to 85% vs 80 to 86% at 4 weeks).

One week of triple therapy with pantoprazole (40mg twice daily), clarithromycin (500mg 3 times daily) and metronidazole (500mg 3 times daily) in patients with H. pylori-associated duodenal ulcer achieved an eradication rate of 97% and duodenal ulcer healing in 98% of patients after 4 weeks. Administration of pantoprazole (40mg twice daily), clarithromycin (500mg twice daily) and metronidazole (500mg twice daily) produced H. pylori eradication in all patients with H. pylori associated gastrointestinal disease (n = 25). An eradication rate of 86% was achieved after 5 weeks using 7- to 10-day triple therapy with the same dosage of pantoprazole but lower dosages of clarithromycin (250mg twice daily) and either metronidazole (400mg twice daily) or tinidazole (500mg twice daily).

Tolerability

Pantoprazole has been well tolerated in short term (≤ 8 weeks) and long term studies (up to 4 years) when administered at the standard dosage of 40mg once daily or higher dosages (up to 120 mg/day) to patients with acid-related disorders. On short term administration, the most frequent adverse events with the drug included diarrhoea (1.5%), headache (1.3%), dizziness (0.7%), pruritus (0.5%) and skin rash (0.4%). These were generally of mild or moderate intensity, rarely necessitating treatment withdrawal, and were no more frequent with pantoprazole than with standard dosages of ranitidine and omeprazole. Clinically relevant alterations in routine laboratory parameters have not been noted on short term therapy.

Limited long term (6 months to 4 years) tolerability data in patients with peptic ulcer indicated that pantoprazole was without significant adverse effects, apart from an episode of peripheral oedema which resolved on drug withdrawal, and did not increase enterochromaffin-like (ECL) cell density.

Dosage and Administration

Pantoprazole is available as a 40mg enteric-coated tablet for once daily oral administration. Dosage modification is not required in the elderly or in patients with renal or hepatic impairment.

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Correspondence to Lynda Wiseman.

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Various sections of the manuscript reviewed by: G. Brunner, Medizinische Hochschule Hannover, Abt für Gastroenterologie und Hepatologie, Hannover, Germany; G. Dobrilla, Divisione di Gastroenterologia, Ospedale Generale Regionale, Bolzano, Italy; C. Howden, Division of Digestive Diseases and Nutrition, The University of South Carolina, Columbia, South Carolina, USA; G. Judmaier, Clinic of Internal Medicine, Department of Gastroenterology, Innsbruck, Austria; U. Klotz, Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany; H. Koop, 4th Department of Medicine, Klinikum Buch, Berlin, Germany; T. Miwa, Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan; J. Mössner, Zentrum für Innere Medizin, Medizinische Klinik und Poliklinik II, Universität Leipzig, Leipzig, Germany; F.O. Müller, FARMOVS Institute for Clinical Pharmacology and Drug Development, Department of Pharmacology, University of the Orange Free State, Bloemfontein, South Africa; G. Sachs, Department of Physiology and Medicine, Wadsworth VAMC and ACLA Medical Center, Los Angeles, California, USA; B. Simon, Facharzt für Innere Medizin-Gastroenterologie, Krankenhaus Schwetzingen, Schwetzingen, Germany; C.J. van Rensburg, Gastroenterology Unit, Department of Internal Medicine, Tygerberg Hospital, Tygerberg, South Africa.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259131.

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Fitton, A., Wiseman, L. Pantoprazole. Drugs 51, 460–482 (1996). https://doi.org/10.2165/00003495-199651030-00012

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Keywords

  • Omeprazole
  • Duodenal Ulcer
  • Ranitidine
  • Lansoprazole
  • Famotidine