7 days for acid suppression. The occurrence of rebleeding within 3 days was 5.9% in the Nexium treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleeding in the Nexium treated versus the placebo treated group was 7.7% vs 13.6%.
Other effects related to acid inhibition
During treatment with antisecretory drugs, serum gastrin increases in response to the decreased acid secretion. Chromogranin A (CgA) also increases due to decreased gastric acidity.
An increased number of ECL cells possibly related to the increased serum gastrin levels, have been observed in some patients during long-term treatment with esomeprazole.
During long-term treatment with antisecretory drugs, gastric glandular cysts have been reported to occur at a somewhat increased frequency. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter.
In two studies with ranitidine as an active comparator, Nexium showed better effect in healing of gastric ulcers in patients using NSAIDs, including COX-2 selective NSAIDs.
In two studies with placebo as comparator, Nexium showed better effect in the prevention of gastric and duodenal ulcers in patients using NSAIDs (aged >60 and/or with previous ulcer), including COX-2 selective NSAIDs
5.2 Pharmacokinetic properties
Absorption and distribution
Esomeprazole is acid labile and is administered orally as enteric-coated granules. In vivo conversion to the R-isomer is negligible. Absorption of esomeprazole is rapid, with peak plasma levels occurring approximately 1-2 hours after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once-daily administration. For 20 mg esomeprazole the corresponding values are 50% and 68%, respectively. The apparent volume of distribution at steady state in healthy subjects is approximately 0.22 L/kg body weight. Esomeprazole is 97% plasma protein bound.
Food intake both delays and decreases the absorption of esomeprazole although this has no significant influence on the effect of esomeprazole on intragastric acidity.
Metabolism and excretion
Esomeprazole is completely metabolised by the cytochrome P450 system (CYP). The major part of the metabolism of esomeprazole is dependent on the polymorphic CYP2C19, responsible for the formation of the hydroxy- and desmethyl metabolites of esomeprazole. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the formation of esomeprazole sulphone, the main metabolite in plasma.
The parameters below reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 17 L/h after a single dose and about 9 L/h after repeated administration. The plasma elimination half-life is about 1.3 hours after repeated once-daily dosing. The pharmacokinetics of esomeprazole has been studied in doses up to 40 mg b.i.d. The area under the plasma concentration-time curve increases with repeated administration of esomeprazo
