Pharmacotherapeutic Group: Proton-pump inhibitor. ATC Code: A02BC05.
Pharmacology: Pharmacodynamics: Esomeprazole is the S-isomer of omeprazole and reduces gastric acid secretion through a specific targeted mechanism of action. It is a specific inhibitor of the acid pump in the parietal cell. Both the R- and S-isomer of omeprazole have similar pharmacodynamic activity.
Site and Mechanism of Action: Esomeprazole is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme hydrogen-potassium (H+K+)-ATPase, the acid pump, and inhibits both basal and stimulated acid secretion.
Effect on Gastric Acid Secretion: After oral dosing with esomeprazole 20 mg and 40 mg, the onset of effect occurs within 1 hr. After repeated administration with esomeprazole 20 mg once daily for 5 days, mean peak acid output after pentagastrin stimulation is decreased by 90% when measured 6-7 hrs after dosing on day 5.
After 5 days of oral dosing with esomeprazole 20 mg and 40 mg, intragastric pH >4 was maintained for a mean time of 13 hrs and 17 hrs, respectively, over 24 hrs in symptomatic gastroesophageal reflux disease (GERD) patients. The proportion of patients maintaining an intragastric pH >4 for at least 8, 12 and 16 hrs, respectively, were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
Using area under the concentration-time curve (AUC) as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
Therapeutic Effects of Acid Inhibition: Healing of reflux esophagitis with esomeprazole 40 mg occurs in approximately 78% of patients after 4 weeks and in 93% after 8 weeks.
Tablet: One (1) week treatment with esomeprazole 20 mg twice daily and appropriate antibiotics, results in successful eradication of Helicobacter pylori in approximately 90% of patients. After eradication treatment for 1 week, there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
In a randomized, double-blind, placebo-controlled clinical study, patients with endoscopically confirmed peptic ulcer bleeding characterised as Forrest Ia, Ib, IIa or IIb (9%, 43%, 38% and 10%, respectively) were randomized to receive Nexium solution for infusion (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either esomeprazole 80 mg as an IV infusion over 30 min followed by a continuous infusion of 8 mg/hr or placebo for 72 hrs. After the initial 72-hr period, all patients received open-label oral Nexium 40 mg for 27 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 7.7% versus 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 and, in hospitalized patients, possibly Clostridium difficile.
Tablet: In 2 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 2 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.
Granules: Pediatric GERD- 1 to 11 Years of Age: In a multicenter, parallel-group study, 109 pediatric patients with endoscopically proven GERD (1-11 years of age) were treated with Nexium once daily for up to 8 weeks to evaluate safety and tolerability. Dosing by patient weight was as follows: weight <20 kg: once daily treatment with esomeprazole 5 mg or 10 mg; weight ≥20 kg: once daily treatment with esomeprazole 10 mg or 20 mg.
Patients were endoscopically characterized as to the presence or absence of erosive esophagitis. Fifty-three (53) patients had erosive esophagitis at baseline. Of the 45 patients who had follow-up endoscopy, 43 (93.3%) of these patients had their erosive esophagitis healed through 8 weeks.
GERD- 0 to 11 months of age: In a placebo-controlled study (98 patients aged 1 11 months) efficacy and safety in patients with signs and symptoms of GERD were evaluated. Esomeprazole 1 mg/kg once daily was given for 2 weeks (open-label phase) and 80 patients were included for an additional 4 weeks (double-blind, treatment-withdrawal phase). There was no significant difference between esomeprazole and placebo for the primary endpoint time to discontinuation due to symptom worsening.
In a placebo-controlled study (52 patients aged <1 month) efficacy and safety in patients with symptoms of GERD were evaluated. Esomeprazole 0.5 mg/kg once daily was given for a minimum of 10 days. There was no significant difference between esomeprazole and placebo in the primary endpoint, change from baseline of number of occurrences of symptoms of GERD.
Results from the paediatric studies further show that 0.5 mg/kg and 1.0 mg/kg esomeprazole in <1 month old and 1-11 month old infants, respectively, reduced the mean percentage of time with intra-oesophageal pH <4.
The safety profile appeared to be similar to that seen in adults.
Pharmacokinetics: 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 hrs after dose. The absolute bioavailability is 64% after a single dose of 40 mg and increases to 89% after repeated once-daily administration. For esomeprazole 20 mg, 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 P-450 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 following parameters reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, extensive metabolisers.
Total plasma clearance is about 17 L/hr after a single dose and about 9 L/hr after repeated administration. The plasma elimination half-life (t½) is about 1.3 hrs after repeated once-daily dosing. The pharmacokinetics of esomeprazole has been studied in doses up to 40 mg twice daily. The AUC increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a more than dose proportional increase in AUC after repeated administration. This time- and dose-dependency is due to a decrease of first-pass metabolism and systemic clearance probably caused by an inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite. Esomeprazole is completely eliminated from plasma between doses with no tendency for accumulation during once-daily administration.
The major metabolites of esomeprazole have no effect on gastric acid secretion. Almost 80% of an oral dose of esomeprazole is excreted as metabolites in the urine, the remainder in the faeces. Less than 1% of the parent drug is found in urine.
Special Patient Populations: Approximately 2.9±1.5% of the population lack a functional CYP2C19 enzyme and are called poor metabolisers. In these individuals, the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once-daily administration of esomeprazole 40 mg, the mean AUC was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations (Cmax) were increased by about 60%.
These findings have no implications for the dosage of esomeprazole.
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years).
Following a single dose of esomeprazole 40 mg, the mean AUC is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. These findings have no implications for the dosage of esomeprazole.
Impaired Organ Function: The metabolism of esomeprazole in patients with mild to moderate liver dysfunction may be impaired. The metabolic rate is decreased in patients with severe liver dysfunction resulting in a doubling of the AUC of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe dysfunction. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.
No studies have been performed in patients with decreased renal function. Since the kidney is responsible for the excretion of the metabolites of esomeprazole but not for the elimination of the parent compound, the metabolism of esomeprazole is not expected to be changed in patients with impaired renal function.
Pediatric: Adolescents 12-18 years: Following repeated dose administration of esomeprazole 20 mg and 40 mg in adolescents 12-18 years, the total exposure (AUC) and the time to reach maximum plasma drug concentration (tmax) was similar to that in adults for both esomeprazole doses.
Granules: Children 1-11 years: Following repeated-dose administration of esomeprazole 10 mg, the total exposure (AUC) was similar within the age range 1-11 years and the exposure was similar to the exposure seen with the 20-mg dose in adolescents and adults.
Following repeated dose administration of esomeprazole 20 mg, the total exposure (AUC) was higher in 6-11 years compared to the same dose in adolescents and adults.