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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 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 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 above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hrs in symptomatic gastroesophageal reflux disease (GERD) patients. The proportion of patients maintaining an intragastric pH above 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 curve (AUC) as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
Peprazom IV: During intravenous administration of 80 mg esomeprazole as a bolus Infusion over 30 minutes followed by a continuous Intravenous infusion of 8 mg/h for 23.5 hours, intragastric pH above 4, and pH above 6 was maintained for a mean time of 21 hours, and 11-13 hours, respectively, over 24 hours in healthy subjects.
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.
One (1) week treatment with esomeprazole 20 mg twice daily and appropriate antibiotics, results in successful eradication of H. 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 characterized as forrest la, lb, lla or llb (9%, 43%, 38% and 10%, respectively) were randomized to receive esomeprazole solution for infusion (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either esomeprazole 80 mg as an IV infusion over 30 mins 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 esomeprazole 40 mg orally for 27 days for acid suppression. The occurrence of rebleeding within 3 days was 5.9% in the esomeprazole treated group compared to 10.3% for the placebo group. At 30 days post-treatment, the occurrence of rebleeding in the esomeprazole 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.
An increased number of Enterochromaffin-like (ECL) cells possibly related to the increased serum gastrin levels, has 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 eg, Salmonella and Campylobacter.
In 2 studies with ranitidine as an active comparator, esomeprazole showed better effect in healing of gastric ulcers in patients using nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-2 (COX-2) selective NSAIDs.
In 2 studies with placebo as comparator, esomeprazole 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.
Pharmacokinetics: Absorption and distribution: Peprazom: 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.
Distribution: Peprazom IV: 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,
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 parameters below 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 area under the plasma concentration-time curve (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.
Peprazom IV: Following repeated doses of 40 mg administered as intravenous injections, the mean peak plasma concentration is approx. 13.6 micromol/L. The mean peak plasma concentration after corresponding oral doses is approx. 4.6 micromol/L. A smaller increase (of approximately 30%) can be seen in total exposure after intravenous administration compared to oral administration. There is a dose-linear increase in total exposure following intravenous administration of esomeprazole as a 30-minute infusion (40 mg, 80 mg or 120 mg) followed by a continuous infusion (4 mg/h or 8 mg/h) over 23.5 hours.
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 of age).
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.
Peprazom IV: 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 total exposure of esomeprazole. Therefore, a maximum dose of 20 mg should not be exceeded in GERD patients with severe dysfunction. For patients with bleeding ulcers and severe liver impairment, following an Initial bolus dose of 80 ring, a maximum continuous intravenous infusion dose of 4 mg/h for 71.5 hours may be sufficient. Esomeprazole or its major metabolites do not show any tendency to accumulate will) 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.
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: Peprazom: Adolescents 12-18 years: Following repeated-dose administration of esomeprazole 20 mg and 40 mg. the total exposure (AUC) and the time to reach maximum plasma drug concentration (tmax) in 12-18 years was similar to that in adults for both esomeprazole doses.
Peprazom IV: In a randomized, open-label, multi-national, repeated dose study, esomeprazole was given as a once-daily 3-minute Injection over four days. The study included a total of 59 paediatric patients 0 to 18 years old of which 50 patients (7 children in the age group 1 to 5 years) completed the study and were evaluated for the pharmacokinelics of esomeprazole.
The table below describes the systemic exposure to esomeprazole following the intravenous administration as a 3-minute Injection in paediatric patients and adult healthy subjects. The values in the table are geometric means (range). The 20 mg dose for adults was given as a 30-minute infusion. The Css, max was measured 5 minutes post-dose in all paediatric groups and 7 minutes post-dose in adults on the 40 mg dose, and after stop of infusion In adults on the 20 mg dose. (See Table 1.)
Click on icon to see table/diagram/imageModel based predictions Indicate that following intravenous administration of esomeprazole as a 10-minute, 20-minute and 30-minute Infusions will be reduced by on average 37% to 49%, 54°/. to 66% and 61% to 72%, respectively, across all age and dose groups compared to when the dose is administered as a 3-minute injection.
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 orally administered esomeprazole.
During long-term oral 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 hospitalised patients, possibly also Clostridium difficile.
Paediatric population: 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 orally 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 printery 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 orally 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 to 11 month old infants, respectively, reduced the mean percentage of lime with intra-oesophageal pH < 4.
The safety profile appeared to be similar to that seen in adults.
In a study in paediatric GERD patients (<1 to 17 years of age) receiving long-term PPI treatment, 61% of the children developed minor degrees of ECL cell hyperplasia with no known clinical significance and with no development of atrophic gastritis or carcinoid tumours.
Toxicology: Preclinical Safety Data: Preclinical bridging studies reveal no particular hazard for humans based on conventional studies of repeated-dose toxicity, genotoxicity and toxicity to reproduction. Carcinogenicity studies in the rat with the racemic mixture have shown gastric enterochromaffin-like (ECL)-cell hyperplasia and carcinoids. These gastric effects in the rat are the result of sustained, pronounced hypergastrinaemia secondary to reduced production of gastric acid and are observed after long-term treatment in the rat with inhibitors of gastric acid secretion.
