Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: PHARMACARE LIMITED, Healthcare Park, Woodlands Drive, Woodmead, 2191
Category and Class: A 11.4.3 Medicines acting on gastro-intestinal tract
Pharmacotherapeutic group: Proton pump inhibitors
ATC code: A02BC05
Esomeprazole, the S-isomer of omeprazole, reduces gastric acid secretion through specific inhibition of the acid pump in the parietal cell, where it is concentrated and converted to the active form in the acidic environment of the secretory canaliculi and inhibits the enzyme H+K+ - ATPase – the acid pump. This effect on the final step of the gastric acid secretion is dose-dependent and provides for effective inhibition of both basal and stimulated acid secretion.
After oral dosing with esomeprazole 20 mg and 40 mg the onset of effect occurs within 1 hour. After repeated administration with 20 mg esomeprazole once daily for 5 days, mean peak acid output after pentagastrin stimulation is decreased by 90% when measured 6 to 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 Gastro-oesophageal Reflux Disease (GORD) patients. The proportion of patients maintaining an intragastric pH above 4 for at least 8, 12 and 16 hours were 76%, 54% and 24% respectively for esomeprazole 20 mg. Corresponding proportions for esomeprazole 40 mg were 97%, 92% and 56% respectively.
Using AUC as a surrogate parameter for plasma concentration, a relationship between inhibition of acid secretion and exposure has been shown. Food intake had no significant influence on the effect of esomeprazole on intragastric acidity.
During treatment with antisecretory medicines serum gastrin increases in response to the decreased acid secretion.
During long-term treatment with antisecretory medicines gastric glandular cysts occur. These changes are a physiological consequence of pronounced inhibition of acid secretion, are benign and appear to be reversible.
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 to 2 hours after dose
The absolute bioavailability is 89% after repeated once-daily administration. The apparent volume of distribution at steady state in healthy subjects is approximately 0, 22 litres per kg body weight.
Esomeprazole is 97% plasma protein bound.
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 litres per hour after a single dose and about 9 litres per hour 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.
Approximately 1-2% 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%.
The metabolism of esomeprazole is not significantly changed in elderly subjects (71 to 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.
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 area under the plasma concentration-time curve 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.
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 compound is found in urine.
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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
