CLINICAL PHARMACOLOGY
Pharmacokinetics and Metabolism
Following the administration of 30 mg of lansoprazole by intravenous infusion over 30 minutes to healthy subjects, plasma concentrations of lansoprazole declined exponentially with a mean (± standard deviation) terminal elimination half-life of 1.3 (± 0.5) hours. The mean peak plasma concentration of lansoprazole (Cmax) was 1705 (± 292) ng/mL and the mean area under the plasma concentration versus time curve (AUC) was 3192 (± 1745) ng∙h/mL. The absolute bioavailability of lansoprazole following oral administration is over 80%, and Cmax and AUC of lansoprazole are approximately proportional in doses from 15 mg to 60 mg after single oral administration. The pharmacokinetics of lansoprazole did not change with time after 7-day once daily repeated oral or intravenous administration of 30 mg lansoprazole.
Distribution
The apparent volume of distribution of lansoprazole is approximately 15.7 (± 1.9) L, distributing mainly in extracellular fluid. Lansoprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.05 to 5.0 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 an intravenous dose of lansoprazole, the mean clearance was 11.1 (± 3.8) L/h. 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
Following oral administration, 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. No intravenous dosage adjustment is needed.
Pediatric
The pharmacokinetics of intravenous lansoprazole have not been studied in pediatric patients. For further information, please see the PREVACID package insert for the oral formulations.
Gender
The pharmacokinetic data of intravenous lansoprazole in females is limited; however, in a study with oral lansoprazole comparing 12 male and 6 female human subjects, no gender differences were found in pharmacokinetics and intragastric pH results. No intravenous dosage adjustment is needed. (Also refer to Use in Women.)
Renal Insufficiency
In patients with severe renal insufficiency, plasma protein binding decreased by 1.0%-1.5% after oral administration of 60 mg 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 intravenous dosage 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 after oral administration. An increase in mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Intravenous dose reduction in patients with severe hepatic disease should be considered.
Race
The pooled mean pharmacokinetic parameters of orally administered 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. Information for intravenous dosing is not available.
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 for at least 24 hours irrespective of the stimulus.
Antisecretory Activity
Acid Output
An open-label, single-center, two period study was conducted to evaluate the pharmacodynamics of 30 mg of intravenous lansoprazole and 30 mg of oral lansoprazole in 29 healthy subjects. The primary pharmacodynamic endpoints were pentagastrin stimulated maximum acid output (MAO) and basal acid output (BAO). Subjects received oral lansoprazole for 7 days in Period 1 and then were immediately switched to intravenous lansoprazole for 7 days in Period 2. MAO and BAO were measured at baseline and 21 hours following the last oral dose and the last intravenous dose of lansoprazole. This study demonstrated that 7 days of oral lansoprazole followed by 7 days of intravenous lansoprazole administration significantly suppressed gastric acid output as compared with baseline. Seven days of 30 mg of intravenous lansoprazole was equivalent to 30 mg of oral lansoprazole in the ability to maintain gastric acid output suppression.
Acid Output (mEq/hr) | PREVACID 30 mg |
|---|
| Baseline | After 7 Days of
Oral Dosing | After 7 Days of
I.V. Dosing |
|---|
| Maximum Acid Output (Median) | 11.26
n=27 | 4.76Significantly (p ≤ 0.05) less acid output as compared to baseline.
n=28 | 5.13
n=28 |
| Basal Acid Output (Median) | 1.42
n=28 | 0.42
n=28 | 0.27
n=28 |
24-Hour Intragastric pH
A multiple-dose study was conducted in 36 healthy subjects comparing the pharmacokinetics and pharmacodynamics of lansoprazole after intravenous administration and oral administration. During the first-hour post-dosing interval, intravenous lansoprazole resulted in significantly higher mean intragastric pH than did oral lansoprazole. There were no statistically significant differences between oral and intravenous regimens in 24-hour mean intragastric pH for the percentage of time that the intragastric pH was above 3 and 4 after 1-day or 5-day once daily repeated administration of 30 mg lansoprazole. Gastric acid suppression was maintained throughout each treatment period. The pharmacodynamic results are summarized in the table below.
Mean Antisecretory Effects after Single and Multiple Daily Dosing | Parameter | Baseline Value | PREVACID |
|---|
| 30 mg q.d. Orally x 5 days | 30 mg I.V. Infusion q.d. x 5 Days |
|---|
| Day 1 | Day 5 | Day 1 | Day 5 |
|---|
| Mean 24-Hour pH | 3.33 | 4.75 | 5.25 | 4.86 | 5.36 |
| Mean first hour pH | 4.44 | 2.74 | 4.79 | 4.64Significantly (p≤ 0.05) higher than the oral lansoprazole | 5.91 |
| % Time Gastric pH>3 | 45.27 | 74.08 | 83.92 | 78.36 | 85.54 |
| % Time Gastric pH>4 | 31.07 | 67.18 | 77.61 | 70.51 | 79.68 |
Refer to CLINICAL PHARMACOLOGY for pharmacokinetic results.
Enterochromaffin-like (ECL) Cell Effects
During lifetime exposure of rats with up to 150 mg/kg/day of lansoprazole dosed orally seven days per week, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats. (Refer to PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility.)
Gastric biopsy specimens from the body of the stomach from approximately 150 patients treated continuously with lansoprazole for at least one year did not show evidence of ECL cell effects similar to those seen in rat studies. Longer term data are needed to rule out the possibility of an increased risk of the development of gastric tumors in patients receiving long-term therapy with lansoprazole.
Other Gastric Effects In Humans
Lansoprazole did not significantly affect mucosal blood flow in the fundus of the stomach. Due to the normal physiologic effect caused by the inhibition of gastric acid secretion, a decrease of about 17% in blood flow in the antrum, pylorus, and duodenal bulb was seen. Lansoprazole significantly slowed the gastric emptying of digestible solids. Lansoprazole increased serum pepsinogen levels and decreased pepsin activity under basal conditions and in response to meal stimulation or insulin injection. As with other agents that elevate intragastric pH, increases in gastric pH were associated with increases in nitrate-reducing bacteria and elevation of nitrite concentration in gastric juice in patients with gastric ulcer. No significant increase in nitrosamine concentrations was observed.
Serum Gastrin Effects
In over 2,100 patients, median fasting serum gastrin levels increased 50% to 100% from baseline but remained within normal range after treatment with lansoprazole given orally in doses of 15 mg to 60 mg. These elevations reached a plateau within two months of therapy and returned to pretreatment levels within four weeks after discontinuation of therapy.
Endocrine Effects
Human studies for up to one year have not detected any clinically significant effects on the endocrine system. Hormones studied include testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), prolactin, cortisol, estradiol, insulin, aldosterone, parathormone, glucagon, thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and somatotropic hormone (STH). Lansoprazole in oral doses of 15 to 60 mg for up to one year had no clinically significant effect on sexual function. In addition, lansoprazole in oral doses of 15 to 60 mg for two to eight weeks had no clinically significant effect on thyroid function.
In 24-month carcinogenicity studies in Sprague-Dawley rats with daily dosages up to 150 mg/kg, proliferative changes in the Leydig cells of the testes, including benign neoplasm, were increased compared to control rates; these findings are rat specific.
Other Effects
No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular or respiratory systems have been found in humans. No visual toxicity was observed among 56 patients who had extensive baseline eye evaluations, were treated with up to 180 mg/day of lansoprazole and were observed for up to 58 months.
Other rat-specific findings after lifetime exposure included focal pancreatic atrophy, diffuse lymphoid hyperplasia in the thymus and spontaneous retinal atrophy.
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