Esomeprazole

Esomeprazole (Nexium®; S-omeprazole) is a single optical isomer proton-pump inhibitor (PPI) approved for the management of reflux oesophagitis, the symptomatic treatment of gastro-oesophageal reflux disease (GORD), the prevention and healing of NSAID-associated gastric ulcer disease (and the prevention of NSAID-associated duodenal ulcers in the UK), the treatment of Helicobacter pylori infection and associated duodenal ulcer disease (and prevention of relapse of H. pylori-associated peptic ulcers in the UK), and the treatment of Zollinger-Ellison syndrome (and other hypersecretory syndromes in the US).

Once-daily oral esomeprazole 40 mg demonstrates greater antisecretory activity than other PPIs. Overall, in well designed clinical studies of 4 weeks’ to 6 months’ duration in patients with GORD, esomeprazole had similar or better efficacy than other agents. In patients requiring ongoing treatment with NSAIDs, co-therapy with once-daily esomeprazole 20 or 40 mg achieved relief of gastrointestinal symptoms or prevented ulcer occurrence, more effectively than placebo. Esomeprazole was also better than ranitidine 150 mg twice daily in healing NSAID-associated gastric ulcers. In addition, the drug has demonstrated efficacy as part of a triple-therapy regimen for the eradication of H. pylori infection, the healing of H. pylori associated duodenal ulcers and the prevention of relapse of gastric ulcers. Esomeprazole also effectively treated patients with Zollinger-Ellison syndrome. Esomeprazole is generally well tolerated with an adverse-event profile similar to that of other PPIs. Thus, the efficacy and tolerability of esomeprazole for the management of GORD and H. pylori eradication remains undisputed, and the data support its use for the first-line treatment of NSAID-associated gastric ulcer disease and Zollinger-Ellison syndrome.

Esomeprazole provides gastric and oesophageal mucosal protection through suppression of gastric acid secretion via inhibition of the H⁺/K⁺-adenosine triphosphatase enzyme (proton pump) in gastric parietal cells. This activity involves protonation and conversion of esomeprazole to the active inhibitor, achiral sulphenamide. A subsequent reaction with cysteines results in the inhibition of the proton pump and blocking of the final step in acid production, thereby increasing intragastric pH.

Esomeprazole is rapidly absorbed, with peak plasma levels occurring ≈1 hour after oral administration. Concomitant food intake delays and reduces absorption. Systemic exposure, as measured by the area under the plasma concentration-time curve, is dose-related after single doses and increases in a nonlinear manner with repeated doses. Systemic exposure is higher with esomeprazole than with omeprazole. Esomeprazole is 97% protein bound in plasma and, in healthy volunteers, the apparent volume of distribution at steady state is ≈16 L.

Esomeprazole is extensively metabolized via cytochrome P450 (CYP) isoenzymes, primarily CYP2C19 and CYP3A4. About 80% of each dose is excreted as inactive metabolites in the urine. After repeated daily doses, the mean plasma elimination half-life is ≈1.3 hours.

In patients with healed reflux oesophagitis, esomeprazole 20 mg once daily effectively maintained healing over 6 months. Overall, the proportion of patients with maintained endoscopic and symptomatic remission at 6 months with esomeprazole (83–93%) was better than that with lansoprazole and similar to, or better than, that with pantoprazole. Once-daily esomeprazole 20 mg over 6 months was more effective for the maintenance of healed reflux oesophagitis than esomeprazole 20 mg/day on demand.

Esomeprazole 20 or 40 mg once daily effectively treated chronic heartburn in patients with nonerosive reflux disease (NERD) in large, well designed trials. Heartburn resolution after 4 weeks’ treatment with esomeprazole was achieved in 33–70% of patients. Similar efficacy, as measured by symptom relief, was achieved with once-daily esomeprazole 20 mg, omeprazole 20 mg or pantoprazole 20 mg. Maintenance of symptom resolution in this patient population was achieved over 6 months with esomeprazole 20 mg/day on demand. Significantly fewer patients taking esomeprazole on demand were unwilling to continue therapy for 6 months than patients taking once-daily lansoprazole 15 mg continuously or placebo.

NSAID-associated gastrointestinal symptoms were improved more from baseline, and symptom relief was faster, with esomeprazole 20 or 40 mg once daily than placebo over 4 weeks in well designed studies. In a subgroup analysis, a significant difference in favour of esomeprazole was observed irrespective of whether patients received cyclo-oxygenase-2-selective- or nonselective NSAIDs. Overall, investigator and patient assessments demonstrated greater symptom resolution (i.e. heartburn and acid regurgitation) with esomeprazole than placebo. Maintenance of symptom relief over 6 months in this patient population was more effective with once-daily esomeprazole 20 or 40 mg than with placebo.

Esomeprazole 40 mg once daily was significantly more effective than ranitidine 150 mg twice daily in healing NSAID-associated gastric ulcers after 8 weeks’ treatment. Furthermore, gastric or duodenal ulcer occurrence was prevented in more at-risk patients receiving esomeprazole 20 or 40 mg once daily, in combination with NSAIDs, than in placebo recipients.

Triple therapy regimens including esomeprazole 20 mg twice daily or 40 mg once or twice daily for 7 or 10 days effectively eradicated H. pylori infection in well designed clinical trials. Eradication rates associated with esomeprazole plus clarithromycin and amoxicillin ranged from 74% to 94%. Esomeprazole-based regimens effectively healed patients with H. pylori-associated duodenal ulcers and prevented gastric ulcer relapse.

In patients with Zollinger-Ellison syndrome or idiopathic gastric acid hypersecretion, gastric acid output was controlled in 19 of 21 (90%) patients after 12 months’ treatment with high-dose esomeprazole (most patients received 40 mg twice daily).

In patients with functional or uninvestigated dyspepsia experiencing epigastric pain or burning, once-daily esomeprazole 40 mg for 8 weeks was more effective than placebo in relieving symptoms. The response to a 1-week acid suppression trial in these patients was of limited clinical value in predicting response rates to an additional 7 weeks of esomeprazole treatment.

Following symptom resolution with acute treatment, health-related quality of life (HR-QOL) was maintained more effectively with continuous esomeprazole than on-demand therapy in patients with GORD. HR-QOL was improved more over 4 weeks, and better maintained over 6 months, with esomeprazole than with placebo in patients receiving continuous NSAID therapy.

Once-daily esomeprazole was associated with higher direct costs (year of costing or publication from 2005 onwards), but slightly better efficacy, than comparator PPIs over 8 or 16 weeks of treatment in patients with reflux oesophagitis in European economic analyses using decision models. This resulted in generally acceptable incremental costs per additional week with healed reflux oesophagitis, per additional patient healed or per quality-adjusted life-year (QALY) gained (i.e. cost per QALY gained relative to generic omeprazole was below the commonly accepted threshold of ≈€30 000).

Patient-controlled on-demand esomeprazole was associated with lower direct and societal costs than general practitioner-controlled intermittent esomeprazole or ranitidine in two cost-minimization analyses (year of costing of 2001). Furthermore, in a 6-month modelled cost-effectiveness comparison of on-demand maintenance therapy with various once-daily PPIs in patients with NERD in the UK (year of costing 2003), the number of utilities gained were similar for all the PPIs, but predicted direct costs with on-demand esomeprazole 20 mg were higher than those with rabeprazole 10 mg and pantoprazole 20 mg, and lower than those with lansoprazole 15 mg and omeprazole 20 and 10 mg.

Esomeprazole was generally well tolerated in clinical trials conducted over 4 weeks to 12 months including >17 000 patients. Overall, the type and incidence of adverse effects associated with esomeprazole are similar to those of other frequently used PPIs (omeprazole, lansoprazole, pantoprazole and rabeprazole). In all trials, adverse effects were mostly mild to moderate in severity, and the main effects were headache and diarrhoea, which each occurred in ≈4–5% of patients receiving once-daily treatment. In a large, 4-week trial in patients with reflux oesophagitis, a treatment-related adverse effect occurred in 11% of patients receiving esomeprazole 40 mg once daily and 10% of patients receiving lansoprazole 30 mg once daily, and 1.8% and 1.9% discontinued therapy due to an adverse event.

In a 6-month study in patients receiving treatment for the maintenance of healed reflux oesophagitis, serious adverse events were reported in 3% of patients in each of the once-daily esomeprazole 20 mg and pantoprazole 20 mg treatment groups; one event (in the pantoprazole group) was considered treatment related. A similar proportion of patients in each treatment group discontinued therapy due to an adverse event (1.4% vs 1.3%).

In some placebo-controlled studies of 4 weeks’ to 6 months’ duration in patients with NERD, dyspepsia or who were receiving continuous NSAID therapy, the incidence of adverse events with once-daily esomeprazole 20 or 40 mg was similar to that with placebo.