Nexium/Nexium IV Mechanism of Action

ATC Code: A02B C05.
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: Nexium: After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within one hour. After repeated administration with 20 mg esomeprazole once daily for 5 days, mean peak acid output after pentagastrin stimulation is decreased 90% when measured 6 - 7 hours after dosing on day 5.
After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively over 24 hours in symptomatic GERD patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours respectively were for esomeprazole 20 mg 76%, 54% and 24%. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56%.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown.
Following repeated dose administration of 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, the effect on intragastric pH, expressed as change in percentage of time with intragastric pH>4 from baseline, is similar to that observed after esomeprazole 20 mg in adults. In addition, 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, results in a significant reduction in esophageal acid exposure.
Nexium IV: After 5 days of oral dosing with 20 mg and 40 mg of esomeprazole, intragastric pH above 4 was maintained for a mean time of 13 hours and 17 hours, respectively, over 24 hours in symptomatic GERD patients. The effect is similar irrespective of whether esomeprazole is administered orally or intravenously.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown, after oral administration of esomeprazole.
During intravenous administration of 80 mg esomeprazole as a bolus infusion over 30 minutes followed by a continuous intravenous infusion of 8 mg/hr 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 of oral treatment.
Nexium: One week treatment with esomeprazole 20 mg b.i.d. and appropriate antibiotics, results in successful eradication of Helicobacter pylori in approximately 90% of patients (non US).
After eradication treatment there is no need for subsequent monotherapy with antisecretory drugs for effective ulcer healing and symptom resolution in uncomplicated duodenal ulcers.
In a randomised, double blind, placebo controlled clinical study, 764 patients received 80 mg bolus followed by continuous intravenous infusion of Esomeprazole (NEXIUM) IV for 71.5 hrs followed by continued treatment for 27 days with oral Esomeprazole (NEXIUM) 40 mg. At 7 and 30 days post-treatment, the occurrence of rebleeding was 7.2% in the treatment group vs. 12.9% in the placebo group and 7.7% vs. 13.6%, respectively.
Nexium IV: In a randomized, double blind, placebo-controlled clinical study, 764 patients with bleeding gastric or duodenal ulcers were randomized to receive Esomeprazole (NEXIUM) I.V. for Injection (n=375) or placebo (n=389). Following endoscopic hemostasis, patients received either 80 mg Esomeprazole (NEXIUM) I.V. administered as bolus infusion over 30 minutes followed by a continuous infusion of 8 mg per hour or placebo for 72 hrs. After the initial 72 hour period, all patients received oral Esomeprazole (NEXIUM) 40 mg for 27 days for acid suppression. The occurrence of rebleeding within 3 days was 5.9% in the treatment group compared to 10.3% for the placebo group. At 7 and 30 days post-treatment, the occurrence was 7.2% vs 12.9% and 7.7% vs 13.6%, respectively.
Other effects related to acid inhibition: During treatment with antisecretory drugs serum gastrin increases, in response to the decreased acid secretion. Also chromogranin A (CgA) increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Literature reports indicate that proton pump inhibitor treatment should be stopped 5 to 14 days before CgA measurement. Measurements should be repeated if levels have not normalised by this time.
An increased number of ECL cells, possibly related to the increased serum gastrin levels, have been observed in both children and adults during long term treatment with orally administered esomeprazole. The findings are considered to be of no clinical significance.
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 and, in hospitalized patients, possibly also Clostridium difficile.
Comparative Clinical Trials: In a five-way crossover study, the 24 hour intragastric pH profile of oral esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg once daily was evaluated in 24 symptomatic GERD patients. On day 5, intragastric pH was maintained above 4.0 for a mean of 15.3 hours with esomeprazole, 13.3 hours with rabeprazole, 12.9 hours with omeprazole, 12.7 hours with lansoprazole and 11.2 hours with pantoprazole (p≤0.001 for differences between esomeprazole and all other comparators). Esomeprazole also provided a significantly higher percentage of patients with an intragastric pH greater than 4.0 for more than 12 hours relative to the other proton pump inhibitors (p <0.05).
Nexium: Patients requiring continued NSAID therapy: Treatment of NSAID associated upper gastrointestinal symptoms: Esomeprazole (NEXIUM) was significantly better than placebo in treatment of upper gastrointestinal symptoms in patients using either non-selective or COX-2-selective NSAIDs.
Healing of gastric ulcers associated with NSAID therapy: Esomeprazole (NEXIUM) was significantly better than ranitidine in healing of gastric ulcers in patients using NSAIDs, including COX-2-selective NSAIDs.
Prevention of gastric and duodenal ulcers associated with NSAID therapy in patients at risk: Esomeprazole (NEXIUM) was significantly better than placebo in prevention of gastric and duodenal ulcers associated with NSAID therapy in patients using NSAIDs, including COX-2-selective NSAIDs.
Patients requiring continued low dose aspirin therapy: Prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk.
Esomeprazole (NEXIUM) was significantly better than placebo in prevention of gastric and/or duodenal ulcers associated with low dose aspirin therapy in patients at risk (prior history of ulcer disease, age ≥60 years with a history of coronary artery disease or age ≥65 years).
Nexium IV: Paediatric population: Following repeated oral dose administration of 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, the effect on intragastric pH, expressed as change in percentage of time with intragastric pH>4 from baseline, is similar to that observed after esomeprazole 20 mg in adults. In addition, 0.5 mg/kg and 1.0 mg/kg esomeprazole in < 1 month old and 1 to 11 months old infants, respectively, results in a significant reduction in oesophageal acid exposure.
Pharmacokinetics: Absorption and distribution: Nexium: 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.
Distribution: Nexium 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 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 as follows reflect mainly the pharmacokinetics in individuals with a functional CYP2C19 enzyme, ie, 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 area under the plasma concentration-time curve increases with repeated administration of esomeprazole. This increase is dose-dependent and results in a non-linear dose-AUC relationship 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: Nexium: Approximately 3% 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 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects having a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%.
These findings have no implications for the dosage of Esomeprazole (NEXIUM).
The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).
Following a single dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve 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 (NEXIUM).
The metabolism of esomeprazole in patients with mild to moderate liver impairment may be impaired. The metabolic rate is decreased in patients with severe liver impairment resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in patients with severe hepatic impairment. 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.
Following repeated dose administration of 20 mg and 40 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (t_max) in 12 to 18 year-olds was similar to that in adults for both esomeprazole doses.
Following repeated dose administration of 10 mg and 20 mg esomeprazole, the total exposure (AUC) and the time to reach maximum plasma drug concentration (t_max) for the 10 mg dose was similar across the 1 to 11 years-olds and similar to the total exposure seen with the 20 mg dose in 12 to 18 year-olds and adults. The 20 mg dose resulted in higher exposure in 6 to 11 year-olds compared to 12 to 18 year-olds and adults.
Repeated dose administration of 5 mg esomeprazole resulted in insufficient exposure in 1 to 5 year-olds.
Following repeated dose administration of 1.0 mg/kg esomeprazole in 1 to 11 month old infants, the exposure (AUC) was slightly higher than that observed after 0.5 mg/kg esomeprazole in < 1 month old infants, but similar to that observed after 10 mg in 1 to 11 year-olds, and 20 mg in 12 to 18 year-olds as well as adults.
Nexium IV: CYP2C19 enzyme deficiency: Approximately 3% 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 oral administration of 40 mg esomeprazole, the mean area under the plasma concentration-time curve was approximately 100% higher in poor metabolisers than in subjects with a functional CYP2C19 enzyme (extensive metabolisers). Mean peak plasma concentrations were increased by about 60%. Similar differences have been seen for intravenous administration of esomeprazole.
These findings have no implications for the dosage of esomeprazole.
Age and sex: The metabolism of esomeprazole is not significantly changed in elderly subjects (71 to 80 years of age).
Following a single oral dose of 40 mg esomeprazole the mean area under the plasma concentration-time curve is approximately 30% higher in females than in males. No gender difference is seen after repeated once-daily administration. Similar differences have been seen for intravenous administration of esomeprazole. These findings have no implications for the dosage of esomeprazole.
The pharmacokinetics of esomeprazole in children and adolescents was related to body weight and age (see "Paediatric population" as follows).
Renal insufficiency: 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.
Hepatic insufficiency: The metabolism of esomeprazole in patients with mild to moderate liver impairment may be impaired. The metabolic rate is decreased in patients with severe liver impairment resulting in a doubling of the area under the plasma concentration-time curve of esomeprazole. Therefore, a maximum of 20 mg should not be exceeded in GERD patients with severe impairment. For patients with bleeding ulcers and severe liver impairment, following an initial bolus dose of 80 mg, a maximum continuous intravenous infusion dose of 4 mg/hr may be sufficient in patients with bleeding ulcers. Esomeprazole or its major metabolites do not show any tendency to accumulate with once-daily dosing.
Paediatric population: In a randomized, open-label, multi-national, repeated dose study, esomeprazole was given as a once-daily 3-minute injection in a total of 50 paediatric patients 0 to 17 years old to evaluate the pharmacokinetics of esomeprazole.
The exposure to esomeprazole observed after I.V. esomeprazole 0.5 mg/kg in 0 to 1 month old patients* was lower than that observed with 1.0 mg/kg in 1 to 11 month olds, but similar to that observed with 10 mg in 1 to 5 year olds, 10 mg in 6 to 11 year olds and 20 mg in 12 to 17 year olds. The exposure levels with these doses were higher than that observed with 20 mg Esomeprazole (NEXIUM) I.V. in adults but lower than that with 40 mg Esomeprazole (NEXIUM) I.V. in adults. The exposure to esomeprazole observed after I.V. esomeprazole 1.0 mg/kg in 1 to 11 month olds, 20 mg in 6 to 11 year old patients and 40 mg in 12 to 17 year old patients was similar to that observed with 40 mg Esomeprazole (NEXIUM) I.V. in adults. Model based predictions indicate that C_ss,max following I.V. 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.
* A patient in the age group 0 up to 1 month was defined as a patient with a corrected age of ≥32 complete weeks and < 44 complete weeks, where corrected age was the sum of the gestational age and the age after birth in complete weeks. A patient in the age group 1 to 11 months had a corrected age of ≥44 complete weeks.
Toxicology: Preclinical safety data: Nexium: 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 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.
There was no unexpected toxicity and/or other effects following esomeprazole treatment of rats or dogs from the neonatal period, during suckling and beyond weaning, compared to those previously observed in adult animals. Neither were there any findings indicating that neonatal/juvenile animals are more susceptible to proliferative changes in the gastric mucosa following esomeprazole treatment. Thus, there were no findings in these juvenile toxicity studies that indicate any specific risk in the pediatric population.
Nexium IV: Preclinical studies reveal no particular hazard for humans, based on conventional studies of single and repeated dose toxicity, embryo-foetal toxicity and mutagenicity. As in the oral studies, repeated intravenous administration of esomeprazole to animals resulted in few and primarily mild effects. However, very high intravenous doses caused an acute toxic response that consisted of occasional, nonspecific and short-lived CNS signs. This effect appeared to be associated with the C_max rather than the AUC of esomeprazole. Comparison of the C_max values obtained in humans given 40 mg esomeprazole as a 3-minute injection and the plasma concentrations that were acutely toxic in animals showed a wide margin of safety (at least 6-fold for total and 20-fold for unbound plasma concentrations).
The C_max following a 30 minute infusion of 80 mg esomeprazole in man was very similar to that seen after 40 mg given over 30 minutes. Similar safety margins between the C_max levels in animals and man were seen (at least 5.5-fold for the total and 18-fold for the unbound plasma concentrations).
Comparison of the esomeprazole exposure obtained during continuous intravenous infusion of 8 mg/hr for up to 3 days in man and in continuous infusion of high intravenous doses in dogs for up to 1 month also showed good safety margins: 4.6-fold for the total and 15-fold for the unbound plasma concentrations at steady state (C_ss) and 36-fold for the total and 120-fold for the unbound AUC values over the complete infusion period.
Oral carcinogenicity studies in the rat with the racemic mixture have shown gastric ECL-cell hyperplasia and carcinoids. These gastric effects 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.