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Pharmacology: Tablet: Lansoprazole inhibits the gastric acid secretion strongly and sustainedly by suppressing the activity of (H+,K+)-ATPase which locally exists in the parietal cells of the gastric mucosa and plays an important role as a proton pump.
Clinically, lansoprazole attains a rapid and high healing ratio against gastric and duodenal ulcers, and the usefulness of the drug has been proven. It has also been proved to be useful in the treatment of stomal ulcer, reflux esophagitis and Zollinger-Ellison syndrome.
Pharmacodynamics: Mechanism of Action: Tablet: Lansoprazole 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. 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. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.
IV: Lansoprazole is firstly transferred to the acid-producing region of the gastric mucosal parietal cells, and transformed into an activated form through conversion reaction by acid. This reaction product is considered to combine with the SH-groups of (H+, K+)-ATPase which is locally located in the acid-producing region and playing a role of the proton pump, suppressing the enzyme activity to inhibit the acid secretion.
It has been reported that blood coagulation and platelet aggregation capacities are severely impaired under acidic conditions, and that fibrin formed as a result of blood coagulation is dissolved by pepsin under acidic conditions. Lansoprazole is considered to increase gastric pH, thereby improving blood coagulation and platelet aggregation capacities and inhibiting peptic activity, resulting in suppression of bleeding.
Also, lansoprazole is considered to increase gastric pH by inhibiting acid secretion, thereby promoting repair of injured mucosa, which is inhibited under acidic conditions.
Inhibiting Activity on Gastric Bleeding: In rats (intravenous dose), lansoprazole shows an inhibiting activity on gastric bleeding due to hemorrhagic shock.
Inhibiting Activity on Formation of Gastric Mucosal Injury: In rats (intravenous dose), lansoprazole inhibits gastric mucosal injury due to aspirin or indomethacin.
Inhibiting Activity on Gastric Acid Secretion (24-hour Gastric pH monitoring): By intravenous administration of lansoprazole at a dose of 30 mg twice a day to healthy adults, continuous inhibition of gastric acid secretion is observed. The rates of 24-hour gastric pH 4 holding time (the time that the gastric pH is 4 or over) are similar between IV injection (approximately 3 minutes) and intravenous drip infusion (30 minutes).
In addition, the gastric acid secretion inhibiting effect (pH 4 holding time every 24 hours) after intravenous administration of lansoprazole 30 mg twice a day to healthy adults whose metabolizer types for lansoprazole were identified as EM or PM is as follows: The rates of pH 4 holding time are 56-69% in EMs and 90% in PMs on day 1 and 80-89% in EMs and 98% in PMs on day 5.
Clinical Studies: IV: In clinical trials of PREVACID I.V. in patients with peptic ulcer accompanied by bleeding etc., those in whom hemostasis was observed within 3 days (72 hours) accounted for 94.6% (192/203 patients) of 203 patients who had been evaluated for the hemostatic effect after intravenous administration of 30 mg of this drug twice a day. Of the 203 patients, 41 did not undergo endoscopic pretreatment, while 97.6% of these patients (40/41) had successful hemostasis within 3 days (72 hours).
In the previously mentioned the incidence of adverse events (excluding abnormal changes in laboratory data) was 14.9% (33/221) in the 221 patients intravenously given this drug twice a day.
The incidences of adverse events by background factors of patients were 21.8% (12/55 patients) in females, 33.9% (19/56) in the elderly, and 29.7% (11/37) in patients with body weight of less than 50.0 kg, indicating slightly higher incidences, respectively, compared with 12.7% (21/166) in males, 8.5% (14/165) in the non-elderly, and 14.9% (11/74) in patients with body weight of 50.0 kg or over but less than 60.0 kg, or 10.0% (10/100) in patients with body weight of 60.0 kg or over (excluding those with unknown body weight).
Pharmacokinetics: Tablet: 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 concentrations of lansoprazole (Cmax) and the area under the plasma concentration curve (AUC) of lansoprazole are approximately proportional in doses from 15 mg to 60 mg 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 μg/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 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: One to 17 years of age: The pharmacokinetics of lansoprazole were studies in pediatric patients with GERD aged 1 to 11 years and 12 to 17 years in two separate clinical studies. In children aged 1 to 11 years, lansoprazole was dosed 15 mg q.d. for subjects weighing ≤ 30 kg and 30 mg q.d. for subjects weighing > 30 kg. Mean Cmax and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 mg or 30 mg 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 between the two dose groups in the study. Overall, lansoprazole pharmacokinetic patients aged 1 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 impairment, plasma protein binding decreased by 1.0%-1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment 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 (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function.
Therefore, the pharmacokinetics of lansoprazole were not clinically different in patients with mild, moderate or severe renal impairment compared to healthy subjects with normal renal function.
Hepatic Impairment: In patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment there was an approximate 3-fold increase in mean AUC compared to healthy subjects with normal hepatic function following multiple oral doses of 30 mg PREVACID for 7 days. The corresponding mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 4 hours (Child-Pugh A) or 5 hours (Child-Pugh B).
In patients with compensated and decompensated cirrhosis, there was an approximate 6- and 5-fold increase in AUC, respectively, compared to healthy subjects with normal hepatic function following a single oral dose of 30 mg PREVACID (see Dosage & Administration).
Drug-Drug Interaction: Effect of Lansoprazole on Other Drugs: Cytochrome P450 Interactions: Lansoprazole is metabolized through the cytochrome P450 system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole does not have clinically significant interactions with other drugs metabolized by the cytochrome P450 system such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propanolol, prednisolone, diazepam, clarithromycin, or terfenadine in healthy subjects. These compounds are metabolized through various cytochrome P450 isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A.
Theophylline: When lansoprazole was administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction has not been considered to be clinically concern.
Methotrexate and 7-hydromethotrexate: In an open-label, single-arm, eight-day, pharmacokinetic study of 28 adult rheumatoid arthritis patients (who required the chronic use of 7.5 to 15 mg of methotrexate given weekly), administration of 7 days of naproxen 500 mg twice daily and PREVACID 30 mg daily had no effect on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While this study was not designed to assess the safety of this combination of drugs, no major adverse reactions were noted. However, this study was conducted with low doses of methotrexate. A drug interaction study with high doses of methotrexate has not been conducted.
Amoxicillin: Lansoprazole has also been shown to have no clinically significant interaction with amoxicillin.
Sucralfate: In a single-dose crossover study examining lansoprazole 30 mg administered alone and concomitantly with sucralfate 1 gram, absorption of lansoprazole was delayed and their bioavailability was reduced by 17% when administered concomitantly with sucralfate.
Antacids: In clinical trials, antacids were administered concomitantly with PREVACID and there was no evidence of a change in the efficacy of PREVACID.
Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects who were CYP2C19 extensive metabolizers, receiving once daily administration of clopidogrel 75 mg alone or concomitantly with PREVACID 30 mg (n=40), for 9 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (mean AUC ratio was 86%, with 90% CI of 80 to 92%) when PREVACID was co-administered compared to administration of clopidogrel alone.
Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The effect on exposure to the active metabolite of clopidogrel and on clopidogrel-induced platelet inhibition is not considered clinically important.
Effect of Other Drugs on Lansoprazole: Because lansoprazole is metabolized by CYP2C19 and CYP3A4, inducers and inhibitors of these enzymes may potentially alter exposure of lansoprazole.
IV: Blood concentrations: The serum concentration of lansoprazole after intravenous administration of PREVACID I.V. varies among individuals.
The following figure shows the serum concentration of lansoprazole after intravenous drip of 30 mg of lansoprazole twice a day for 5 days to 12 healthy male adults classified into either extensive metabolizer (EM) group (8 subjects) in which lansoprazole is rapidly metabolized or poor metabolizer (PM) group (4 subjects) in which the drug is slowly metabolized according to CYP2C19 genotype (see Table 1 and Figure).
Protein-Binding Rate: The human serum protein binding rate of lansoprazole at the concentration range of 0.05 to 5 μg/mL is approximately 98%.
Metabolism: Lansoprazole is mainly metabolized by CYP2C19 and CYP3A4. It has been reported that there is genetic polymorphism of CYP2C19, and the frequency of poor metabolizers among Asian-Mongolian populations including Japanese is appoximately 10-20%.
Urinary Excretion: After single intravenous administration lansoprazole 30 mg to healthy male adults (9 subjects), no unchanged compound was detected in the urine; all detected were metabolites. The accumulated urinary excretion rate up to 24 hours after administration was 12-17%.
