Esomeprazole

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.

Distribution

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.

Biotransformation

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.

Elimination

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.

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 medicinal product is found in urine.

Linearity/non-linearity

Total exposure (AUC) 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 inhibition of the CYP2C19 enzyme by esomeprazole and/or its sulphone metabolite.

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 approx 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.

Special patient populations

Poor metabolisers

Approximately 2.9 ±1.5% of the population lacks a functional CYP2C19 enzyme and is called poor metabolisers. In these individuals, the metabolism of esomeprazole is probably mainly catalysed by CYP3A4. After repeated once daily administration of 40 mg oral esomeprazole, the mean total exposure 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 posology of esomeprazole.

Gender

Following a single oral dose of 40 mg esomeprazole the mean total exposure is approximately 30% higher in females than in males. No gender difference is seen after repeated once daily administration. Similar differences have been observed for intravenous administration of esomeprazole. These findings have no implications for the posology of esomeprazole.

Hepatic impairment

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 mg, 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 with once daily dosing.

Renal impairment

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.

Elderly

The metabolism of esomeprazole is not significantly changed in elderly subjects (71-80 years of age).

Paediatric population

In a randomised, 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 pharmacokinetics 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 C_ss,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.

^* 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.
^** Two patients excluded, 1 most likely a CYP2C19 poor metaboliser and 1 on concomitant treatment with a CYP3A4 inhibitor.

Model based predictions indicate that C_ss,max 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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:

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. In the non-clinical program for esomeprazole intravenous formulation there was no evidence of vaso-irritation but a slight tissue inflammatory reaction at the injection site after subcutaneous (paravenous) injection was noted.