Pharmacology: Pharmacodynamics: Mechanism of Action: Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but that suppress gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole 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 gastric acid secretion irrespective of the stimulus.
Serum Gastrin Effects: In over 2100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with 15 to 60 mg of oral lansoprazole. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.
Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors.
Available published evidence suggests that proton pump inhibitors should be discontinued 14 days prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
Pharmacokinetics: PREVACID FDT contains an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. Peak plasma concentration of lansoprazole (Cmax) and the area under the plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15mg to 60mg after single-oral administration. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.
Absorption: The absorption of lansoprazole is rapid, with mean Cmax occurring approximately 1.7 hours after oral dosing, and relatively complete with absolute bioavailability over 80%. In healthy subjects, the mean (±SD) plasma half-life was 1.5 (±1.0) hours. Both Cmax and AUC are diminished by about 50% to 70% if the drug is given 30 minutes after food as opposed to the fasting condition. There is no significant food effect if the drug is given before meals.
Distribution: Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0μg/mL.
Metabolism: Lansoprazole is extensively metabolized in the liver. Two metabolites have been identified in measurable quantities in plasma (the hydroxylated sulfinyl and sulfone derivatives of lansoprazole). These metabolites have very little or no antisecretory activity. Lansoprazole is thought to be transformed into two active species which inhibit acid secretion by (H+, K+)ATPase within the parietal cell canaliculus, but are not present in the systemic circulation. The plasma elimination of half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion. Thus, the plasma elimination half-life is less than two hours, while the acid inhibitory effect lasts more than 24 hours.
Elimination: Following single-dose oral administration of lansoprazole, virtually no unchanged lansoprazole was excreted in the urine. In one study, after a single oral dose of 14C-lansoprazole, approximately one-third of the administered radiation was excreted in the urine and two-thirds was recovered in the feces. This implies a significant biliary excretion of the metabolites of lansoprazole.
Special Populations: Geriatric: The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly.
Pediatric: The pharmacokinetics of lansoprazole were studies in pediatric patients with GERD aged 12 to 17 years. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15mg or 30mg q.d. Mean Cmax and AUC values of lansoprazole was not affected by bodyweight or age; and nearly dose-proportional increases in Mean Cmax and AUC values were observed. Overall, lansoprazole pharmacokinetic patients aged 12 to 17 years were similar to those observed in healthy adult subjects.
Gender: In a study comparing 12 male and 6 female human subjects, no gender differences were found in pharmacokinetics and intragastric pH results.
Renal Insufficiency: In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after administration of 60mg of lansoprazole. Patients with renal insufficiency had a shortened elimination half-life and decreased total AUC (free and bound). AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment, and Cmax and Tmax were not different from subjects with healthy kidneys. No dose adjustment is necessary in patients with renal insufficiency.
Hepatic Insufficiency: In patients with various degrees of chronic hepatic disease, the mean plasma half-life of the drug was prolonged from 1.5 hours to 3.2-7.2 hours. An increase in mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Dose reduction in patients with severe hepatic disease should be considered.
Race: The pooled mean pharmacokinetic parameters of lansoprazole from twelve U.S. Phase 1 studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of lansoprazole in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.