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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.
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.
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 blocking the proton pump [(H+,K+)-ATPase enzyme system] at the secretory surface of the gastric parietal cell. The two active species are not present in the systemic circulation. The plasma elimination half-life of lansoprazole is less than 2 hours while the acid inhibitory effect lasts more than 24 hours. Therefore, the plasma elimination half-life of lansoprazole does not reflect its duration of suppression of gastric acid secretion.
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 lansoprazole metabolites.
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.
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.
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 who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results. No intravenous dosage adjustment is needed (also refer to Use in Women).
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). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the Cmax and Tmax (time to reach the maximum concentration) were not different than the Cmax and Tmax from subjects with normal renal function. No intravenous dosage adjustment is necessary in patients with renal insufficiency.
In patients with various degrees of chronic hepatic disease, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2-7.2 hours after oral administration. An increase in the 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.
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.
Mechanism of Action
PREVACID (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 for at least 24 hours irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.
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 (Table 1).
Table 1: 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
|Basal Acid Output (Median)|| 1.42
|* Significantly (p ≤ 0.05) less acid output as compared to baseline.|
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 Table 2.
Table 2: Mean Antisecretory Effects after Single and Multiple Daily Dosing
|30 mg daily Orally x 5 days||30 mg I.V. Infusion daily x 5 Days|
|Value||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||4.64*||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|
|*Significantly (p≤ 0.05) higher than the oral lansoprazole|
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 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.
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 lansoprazole 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.
No systemic effects of lansoprazole on the central nervous system, lymphoid, hematopoietic, renal, hepatic, cardiovascular or respiratory systems have been found in humans. Among 56 patients who had extensive baseline eye evaluations, no visual toxicity was observed after lansoprazole treatment (up to 180 mg/day) for up to 58 months.
A multicenter, double-blind, two-period placebo-controlled, pharmacodynamic study was conducted to assess the ability of PREVACID I.V. (lansoprazole for injection) for Injection to maintain gastric acid suppression in patients switched from the oral dosage form of lansoprazole to the intravenous dosage form. Erosive esophagitis patients (n=87; 18 to 78 years of age; 28 female; 69 Caucasian/non-Hispanic, 14 Hispanic, 3 African-American, and 1 Native American) received 30 mg of oral lansoprazole for 7 days in Period 1. Patients were then immediately switched to receive either 30 mg of intravenous lansoprazole or intravenous placebo (normal saline) for 7 days in Period 2. MAO and BAO were determined 21 hours following the last dose of oral medication and the last dose of intravenous administration. MAO was calculated from two hours of continuous collection of gastric contents following a subcutaneous injection of 6.0 µg/kg of pentagastrin. BAO was calculated from one hour of continuous collection of gastric contents.
This study demonstrated that, after seven days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of PREVACID were similar in their ability to suppress MAO and BAO in patients with erosive esophagitis (refer to Table 3). Also, patients receiving oral PREVACID, who were switched to intravenous placebo, experienced a significant increase in acid output within 48 hours of their last oral dose.
Table 3: Acid Output (mEq/h) in Erosive Esophagitis Patients
| PREVACID Oral
(last oral dose)
| PREVACID I.V.
(last I.V. dose)
| Placebo I.V.
(last I.V. dose)
| Maximum Acid Output
| Basal Acid Output
|*, ** Significantly different from PREVACID I.V. at p=0.005 and p< 0.001 levels, respectively|
Last reviewed on RxList: 7/11/2007
This monograph has been modified to include the generic and brand name in many instances.
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