Esomeprazole

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Abstract
Esomeprazole, the S-isomer of omeprazole, is the first proton pump inhibitor to be developed as a single optical isomer. It provides better acid control than current racemic proton pump inhibitors and has a favourable pharmacokinetic profile relative to omeprazole. In large well designed 8-week trials in patients with erosive oesophagitis, esomeprazole recipients achieved significantly higher rates of endoscopically confirmed healed oesophagitis than those receiving omeprazole or lansoprazole. Esomeprazole was effective across all baseline grades of oesophagitis; notably, relative to lansoprazole, as the baseline severity of disease increased, the difference in rates of healed oesophagitis also increased in favour of esomeprazole. In two trials, 94% of patients receiving esomeprazole 40mg once daily achieved healed oesophagitis versus 84 to 87% of omeprazole recipients (20mg once daily). In a study in >5000 patients, respective healed oesophagitis rates with once-daily esomeprazole 40mg or lansoprazole 30mg were 92.6 and 88.8%. Resolution of heartburn was also significantly better with esomeprazole than with these racemic proton pump inhibitors. Long-term (up to 12 months) therapy with esomeprazole effectively maintained healed oesophagitis in these patients. Esomeprazole 20 or 40mg once daily for 4 weeks proved effective in patients with symptomatic gastro-oesophageal reflux disease (GORD) without oesophagitis. Eradicating Helicobacter pylori infection is considered pivotal to successfully managing duodenal ulcer disease. Ten days’ triple therapy (esomeprazole 40mg once daily, plus twice-daily amoxicillin 1g and clarithromycin 500mg) eradicated H. pylori in 77 to 78% of patients (intention-to-treat) with endoscopically confirmed duodenal ulcer disease. Esomeprazole is generally well tolerated, both as monotherapy and in combination with antimicrobial agents. The tolerability profile is similar to that of other proton pump inhibitors. Few patients discontinued therapy because of treatment-emergent adverse events (H. pylori infection in patients with duodenal ulcer disease. In 8-week double-blind trials, esomeprazole effectively healed oesophagitis and resolved symptoms in patients with endoscopically confirmed erosive oesophagitis. Notably, in large (n >1900 patients) double-blind trials, esomeprazole provided significantly better efficacy than omeprazole or lansoprazole in terms of both healing rates and resolution of symptoms. Long-term therapy with esomeprazole effectively maintained healed oesophagitis in these patients. Esomeprazole was also effective in patients with symptomatic GORD. Thus, esomeprazole has emerged as an effective option for first-line therapy in the management of acid-related disorders. Esomeprazole inhibits the activity of the H+/K+-ATPase enzyme (the proton pump), and thereby reduces secretion of hydrochloric acid by gastric parietal cells. Superiority of esomeprazole over omeprazole, lansoprazole, rabeprazole and pantoprazole in terms of elevation of intragastric pH has been shown in a number of randomised, crossover trials (most of which were nonblind) in healthy volunteers and patients with symptoms of gastro-oesophageal reflux disease (GORD). On the fifth day of treatment intragastric pH was >4 for a mean 59.4 to 69.8% of the monitored 24-hour periods in individuals receiving esomeprazole 40mg daily. These percentages were significantly greater than those with comparators (43.7 to 62% for once-daily esomeprazole 20mg, omeprazole 20 or 40mg, rabeprazole 20mg, pantoprazole 40mg or lansoprazole 30mg daily). Similarly, esomeprazole 20mg daily was superior to omeprazole 20mg or lansoprazole 15mg daily in the maintenance of gastric pH >4. Higher percentages of patients receiving esomeprazole 20 or 40mg than recipients of other agents maintained intragastric pH >4 for periods ranging from at least 8 hours to more than 16 hours. In one nonblind study in 35 patients with GORD receiving esomeprazole 40mg or rabeprazole 20mg daily, pH was >4 for 23.2 and 11%, respectively, of the first 4 hours after administration of the first dose of study medication, indicating a more rapid onset of reduction of intragastric pH with esomeprazole. Esomeprazole has no apparent effect on a variety of endocrine and metabolic functions but, like other proton pump inhibitors, the drug increases fasting serum gastrin levels in a dose-related fashion. Esomeprazole is absorbed rapidly after oral administration, and areas under curves of plasma drug concentration versus time (AUCs) increase in a nonlinear, dose-related fashion after single doses. Systemic exposure to esomeprazole (as shown by mean AUC extrapolated to infinity, AUC∞) increases with repeated administration of the drug (by 90% with 20mg daily and 159% with 40mg daily relative to day 1 after 5 days’ treatment in healthy volunteers). This effect is attributed to reductions in total body clearance and first-pass metabolism with repeated doses. Binding to plasma proteins of esomeprazole (97%) is similar to that seen with omeprazole and other proton pump inhibitors. Metabolism of esomeprazole is via hepatic cytochrome P 450 (CYP) isoenzymes, chiefly CYP3A4 and CYP2C19, with approximately 80% of each dose being excreted as metabolites in the urine. A small proportion of the population lacks a functional form of the CYP2C19 isoenzyme and are therefore poor metabolisers of esomeprazole. AUC data indicate that dosage adjustments are not necessary in these individuals. Comparative pharmacokinetic data obtained in patients with GORD show similar times to attainment of peak plasma concentrations with esomeprazole and omeprazole (approximately 1 hour). However, after 5 days’ treatment, the geometric mean AUC∞ for esomeprazole 20mg daily was approximately two times higher than that for omeprazole 20mg daily, whereas that for esomeprazole 40mg daily was over five times higher than omeprazole 20mg (p < 0.0001 for both differences) in a study in 36 evaluable patients. There was also less interpatient variability in AUC∞ values with esomeprazole than with omeprazole, although statistical significance was not stated for this finding. Systemic exposure to esomeprazole is not increased sufficiently to warrant tolerability concerns in patients with mild to moderate hepatic insufficiency; maximum plasma concentrations (Cmax) increased 28% in 12 patients with mild (Child-Pugh class A) to severe (Child-Pugh class C) hepatic insufficiency. There are no clinically significant gender effects on the drug’s disposition. The potential for interactions between esomeprazole and other drugs is reported to be low and similar to that with omeprazole. In patients with erosive oesophagitis: In studies of 8 weeks’ duration (the usual duration for these trials), esomeprazole effectively healed oesophagitis (primary efficacy endpoint) and resolved heartburn (secondary endpoint) in patients with GORD in several large, randomised, double-blind, multicentre trials. Patients received oral esomeprazole 20 or 40mg, lansoprazole 30mg or omeprazole 20mg once daily before breakfast. Patients who showed endoscopically confirmed healed oesophagitis were discontinued from the study at 4 weeks. Esomeprazole provided superior efficacy to lansoprazole or omeprazole after 4 to 8 weeks’ treatment, as determined by endoscopically confirmed healed oesophagitis rates. In a large double-blind trial in more than 5000 patients, significantly more recipients of esomeprazole 40mg once daily than lansoprazole 30mg once daily showed healed oesophagitis at 8 weeks (92.6 vs 88.8% of patients; p vs omeprazole) and 40mg (94.1 %; p < 0.001 vs omeprazole) groups than in the omeprazole 20mg group (86.9%). Evidence-based analysis using pooled data from two trials confirmed that esomeprazole was more effective than omeprazole in healing erosive oesophagitis; 11 patients would need to be treated with esomeprazole 40mg once daily rather than omeprazole 20mg once daily to prevent one treatment failure. The higher response rates with esomeprazole treatment relative to omeprazole occurred across all baseline grades of disease severity (based on Los Angeles Classification grades). Furthermore, relative to lansoprazole, as the baseline severity of disease increased, the difference in rates of healed oesophagitis also increased in favour of esomeprazole. Esomeprazole also proved effective in patients with erosive oesophagitis according to secondary efficacy endpoints (e.g. percentage of heartburn-free days and nights, and the time to sustained resolution of symptoms). Heartburn resolution with esomeprazole was significantly better than that of omeprazole for all secondary efficacy endpoints, with a significantly reduced time to complete resolution of heartburn. Furthermore, esomeprazole recipients experienced significantly fewer nights with heartburn relative to lansoprazole (87.1 vs 85.8% of nights heartburn-free; p ≤ 0.05), with complete resolution of symptoms occurring sooner in the esomeprazole group (7 vs 8 days; p ≤ 0.01); there was no between-group difference in the number of days without heartburn. Resolution of heartburn matched healed oesophagitis rates in a post-hoc analysis of pooled data from US 8-week randomised, double-blind trials evaluating 4877 patients. After 4 weeks’ treatment with esomeprazole 40mg once daily, 83.4 and 81 % of recipients who had healed oesophagitis were asymptomatic for heartburn and acid regurgitation, respectively, compared with 75.4 and 71.6% of those receiving omeprazole 20mg once daily (p < 0.001 for both comparisons). Maintenance therapy in patients with GORD: Esomeprazole 20 or 40mg once daily was significantly more effective than placebo in maintaining healed oesophagitis, prolonging the time to recurrence of erosive oesophagitis, in two 6-month randomised, double-blind, multicentre trials. Healed oesophagitis was maintained in 79 and 93% (esomeprazole 20mg), 88 and 94% (esomeprazole 40mg), or 29% (placebo) of patients. Subgroup analyses indicated that maintenance of healing with esomeprazole treatment was not influenced by gender, age (≥65 years vs vs 8 weeks) or baseline severity of erosive oesophagitis. Similar results were reported in a noncomparative trial of 12 months’ duration. Although there was no statistically significant difference in the percentage of patients who were heartburn-free at 6 months with esomeprazole and placebo treatment, this most likely reflects the fact that only patients with maintained healing remained in the study at 6 months. A significantly higher percentage of esomeprazole (20mg once daily) than lansoprazole (15mg once daily) recipients remained in remission (primary end-point) at 6 months in a large, randomised, double blind trial (83 vs 74% of patients; p < 0.001). Esomeprazole recipients showed higher rates of remission across all grades of baseline disease severity than lansoprazole-treated patients. Furthermore, significantly more esomeprazole than lansoprazole recipients were asymptomatic at 6 months [heartburn-free (78 vs 71% of patients), acid regurgitation-free (81 vs 72%) and epigastric pain-free (80 vs 75%)]. In patients with symptomatic GORD without oesophagitis: Esomeprazole 20 or 40mg once daily for 4 weeks effectively resolved symptoms in patients with symptomatic GORD without oesophagitis in randomised double-blind trials. Thirty-three to 42% of patients achieved complete resolution of heartburn (no heartburn during the final 7 days of the 4-week studies) with esomeprazole versus 12 to 14% of placebo recipients. Additionally, 63 to 68% of days were heartburn-free with esomeprazole (20 or 40mg once daily) therapy compared with 36 to 46% with placebo. Respective median times to sustained resolution of heartburn were also significantly shorter in patients receiving esomeprazole (12.1 to 17.3 vs 20.8 to 22.3 days). Eradication of H. pylori infection: Ten days’ triple therapy including esomeprazole 40mg once daily, plus twice daily amoxicillin 1g and clarithromycin 500mg, effectively eradicated H. pylori infection in patients with duodenal ulcer disease. As expected, this esomeprazole-based regimen was significantly (p < 0.001) more effective in eradicating H. pylori infection than 10 days’ dual therapy (esomeprazole plus clarithromycin at the same dosages) [77 vs 52% of patients; intention-to-treat analysis]. Emerging resistance, particularly in the US, to clarithromycin and other antimicrobial agents used in triple therapy regimens is of increasing concern. Of note, pooled data from these two trials plus another small (n = 66) study (dual therapy with the same dosages of esomeprazole plus clarithromycin, or esomeprazole monotherapy) reported in the same publication indicated that 15% of H. pylori clinical isolates collected from patients at baseline were resistant to clarithromycin. Like other proton pump inhibitors, esomeprazole is safe and well tolerated. In two large 8-week randomised trials (n = 2405 and 1957) and in pooled tolerability data (n = 6682), a similar small proportion of patients (≈1 to 2.6% of patients) receiving esomeprazole 20 or 40mg once daily or omeprazole 20mg once daily discontinued treatment due to an adverse event. There was also no difference in the nature or frequency of individual adverse events; headache, diarrhoea, nausea, abdominal pain and respiratory infection were most commonly reported. No treatment-related serious adverse events were reported with esomeprazole or omeprazole therapy in these studies. There were also no clinically relevant changes in laboratory parameters or vital signs with either treatment. There were no between-group differences in the tolerability profiles of esomeprazole 40mg once daily or lansoprazole 30mg once daily in a large randomised, double-blind trial in >5000 patients with erosive oesophagitis. Ten percent of patients in each treatment group experienced at least one adverse event considered to be drug-related; the most frequently reported adverse events with either esomeprazole or lansoprazole treatment were headache (5.8 vs 4.5%), diarrhoea (4.2 vs 4.7%), respiratory infection (2.8 vs 3.8%), abdominal pain (2.9 vs 2.9%), flatulence (2.3 vs 2.4%) and nausea (2.1 vs 2.5%). Serious adverse events considered to be treatment related occurred in 0.7 and 0.5% of patients in the esomeprazole and lansoprazole groups, respectively, with 1.8 and 1.9% of recipients discontinuing treatment due to adverse events. There were no clinically relevant changes in laboratory parameters or vital signs in either treatment group. Triple therapy with esomeprazole plus amoxicillin and clarithromycin for 10 days for the eradication of H. pylori infection was most commonly associated with diarrhoea, taste perversion, and abdominal pain according to pooled tolerability data (number of patients not reported). Maintenance therapy with esomeprazole 20 or 40mg once daily for 6 months was generally well tolerated in patients with healed GORD in two randomised, double-blind studies in 318 and 375 patients. The nature of drug-related adverse events experienced with maintenance treatment was no different from that experienced with 4 to 8 weeks’ treatment. A 12-month noncomparative study in 807 patients with healed oesophagitis confirmed that esomeprazole 40mg once daily was well tolerated. Patients who received esomeprazole as maintenance therapy remained in randomised studies for a much longer time than placebo recipients (mean values: 116 to 161 vs 59 and 61.5 days). Therefore, direct comparisons of adverse event incidences were difficult to make. After 1 month of treatment, the incidences of the most common adverse events and the proportions of patients who experienced at least one adverse event were similar in the esomeprazole and placebo treatment groups. Over the 6 months’ duration of these trials, esomeprazole was generally associated with higher rates of discontinuation due to adverse events and higher overall frequencies of adverse events than placebo, possibly because of the longer treatment time with the active drug. No enterochromaffin-like cell dysplasia, carcinoids or neoplasia were reported in pooled tolerability data from noncomparative and randomised studies in 1326 patients with healed erosive oesophagitis who received esomeprazole 20 or 40mg once daily or placebo for up to 6 or 12 months. Gastric histological scores with both esomeprazole and placebo fluctuated to a minor extent and there were no concerns relating to development of atrophic gastritis or clinically significant changes in enterochromaffin-like cells. In the US, esomeprazole 20 or 40mg once daily for 4 to 8 weeks is indicated for the healing of erosive oesophagitis associated with GORD; if oesophagitis is not healed, a further 4 to 8 weeks’ therapy may be considered. Esomeprazole 20mg once daily is recommended for the maintenance of healed erosive oesophagitis. Currently, no controlled studies of >6 months duration have been carried out; a noncomparative trial of 12 months’ duration has been conducted. In patients with symptomatic GORD, esomeprazole 20mg once daily for 4 weeks is recommended; if symptoms have not resolved, a further 4 weeks’ treatment may be considered. For the eradication of H. pylori in patients with duodenal ulcer disease, triple therapy with esomeprazole 40mg once daily plus amoxicillin 1g twice daily and clarithromycin 500mg twice daily for 10 days is recommended. Esomeprazole capsules should be swallowed whole at least 1 hour before eating; the contents of the capsules (pellets) may be mixed with apple sauce for patients who have difficulty in swallowing. In nursing mothers, a decision should be made whether to discontinue nursing or to discontinue treatment. Although animal studies have shown no evidence of fetal abnormality, there are no well controlled trials in pregnant women (category B rating); thus, the drug should be used during pregnancy only if clearly needed. Dosage adjustments are not necessary in patients who are elderly or in those with renal or mild to moderate hepatic impairment. In patients with severe hepatic impairment, the dosage of esomeprazole should not exceed 20mg daily. The tolerability and effectiveness of esomeprazole have not yet been established in paediatric patients. Concurrent administration of esomeprazole with warfarin, quinidine or amoxicillin does not produce any clinically significant interactions. Esomeprazole may, however, interfere with the absorption of drugs where gastric pH is an important determinant of bioavailability (e.g. ketoconazole, digoxin and iron salts).