Esomeprazole magnesium - How It Works
Clinical pharmacology details from the US FDA-approved label: how Esomeprazole magnesium works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action Esomeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Esomeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell.
Esomeprazole is protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide.
Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, esomeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production.
This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus.
12.2 Pharmacodynamics Antisecretory Activity Adults The effect of esomeprazole on intragastric pH was determined in adult patients with symptomatic GERD in two separate studies.
In the first study of 36 patients, esomeprazole magnesium delayed-release capsules 40 mg and 20 mg delayed-release capsules were administered once daily over 5 days as shown in Table 5: Table 5: Effect of Esomeprazole on Intragastric pH on Day 5 (N=36) Following Once Daily Dosing of Esomeprazole Magnesium Delayed-Release Capsules in Adult Patients with Symptomatic GERD Parameter Esomeprazole Magnesium Delayed-Release Capsules 40 mg once daily 20 mg once daily % Time Gastric pH >4 1 (Hours) 70% 2 (16.8 h) 53% (12.7 h) Coefficient of variation 26% 37% Median 24 Hour pH 4.9 2 4.1 Coefficient of variation 16% 27% Gastric pH was measured over a 24-hour period p< 0.01 esomeprazole magnesium delayed-release capsules 40 mg vs. esomeprazole magnesium delayed-release capsules 20 mg In a second study, the effect on intragastric pH of esomeprazole magnesium delayed-release capsules 40 mg delayed-release capsules administered once daily over a five-day period was similar to the first study, (% time with pH > 4 was 68% or 16.3 hours).
Pediatrics In infants (1 to 11 months old, inclusive) with GERD given esomeprazole magnesium for delayed-release oral suspension 1 mg/kg once daily, the percent time with intragastric pH > 4 increased from 29% at baseline to 69% on Day 7, which is similar to the pharmacodynamic effect in adults.
Serum Gastrin Effects The effect of esomeprazole on serum gastrin concentrations was evaluated in approximately 2,700 patients in clinical trials of oral esomeprazole for up to 8 weeks and in over 1,300 patients for up to 12 months.
The mean fasting gastrin level increased in a dose-related manner.
The increase in serum gastrin concentrations reached a plateau within two to three months of therapy and returned to baseline levels within four weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels.
The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions ] Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3,000 patients (both pediatrics and adults) treated with omeprazole in long-term clinical trials.
The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients [see Nonclinical Toxicology ] In over 1,000 patients treated with oral esomeprazole (10 mg, 20 mg or 40 mg/day) for up to 12 months, the prevalence of ECL cell hyperplasia increased with time and dose.
No patient developed ECL cell carcinoids, dysplasia, or neoplasia in the gastric mucosa.
Endocrine Effects Esomeprazole had no effect on thyroid function in adults when given esomeprazole magnesium delayed-release capsules 20 mg or 40 mg delayed-release capsules once daily for 4 weeks.
Other effects of esomeprazole on the endocrine system were assessed in studies of omeprazole.
Oral doses of omeprazole 30 mg or 40 mg once daily for 2 to 4 weeks had no effect on carbohydrate metabolism, circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin, or secretin.
12.3 Pharmacokinetics Absorption Esomeprazole magnesium delayed-release capsules and esomeprazole magnesium for delayed-release oral suspension showed similar bioavailability after a single dose (40 mg) administration in 94 healthy male and female subjects under fasting conditions.
After oral administration, peak plasma levels (C max ) of esomeprazole occur at approximately 1.5 hours (T max ).
The C max increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentrationtime curve (AUC) from 20 to 40 mg.
Pharmacokinetics
12.3 Pharmacokinetics Absorption Esomeprazole magnesium delayed-release capsules and esomeprazole magnesium for delayed-release oral suspension showed similar bioavailability after a single dose (40 mg) administration in 94 healthy male and female subjects under fasting conditions. After oral administration, peak plasma levels (C max ) of esomeprazole occur at approximately 1.5 hours (T max ). The C max increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentrationtime curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 micromol*hr/L on Day 1 to 11.2 micromol*hr/L on Day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of esomeprazole magnesium delayed-release capsules is decreased by 43% to 53% after food intake compared to fasting conditions [see Dosage and Administration ] . The pharmacokinetics of esomeprazole in adult patients with symptomatic GERD following repeated once daily administration of 20 mg and 40 mg esomeprazole magnesium delayed-release capsules over a period of five days are shown in Table 6: Table 6: Geometric Mean (95% CI) Pharmacokinetic Parameters of Esomeprazole on Day 5 Following Once Daily Dosing of Esomeprazole Magnesium Delayed-Release Capsules in Adult Patients with Sympto