Antaxid Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding in the (HK)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The binding to the (HK)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested.
Antisecretory Activity: Under maximal acid stimulatory conditions using pentagastrin, a dose dependent decrease in gastric acid output occurs after a single dose of oral (20-120 mg) pantoprazole in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once a day dosing for 7 days the mean inhibition was increased to 85%.
Pantoprazole suppressed acid secretion in excess of 95% in half of the subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole, there was no evidence of rebound hypersecretion.
In a series of dose-response studies pantoprazole, at oral doses from 20 to 120 mg, caused dose-related increases in median basal gastric pH and in the percent of time gastric pH was >3 and >4. Treatment with 40 mg of pantoprazole produced optimal increases in gastric pH which were significantly greater than the 20-mg dose. Doses higher than 40 mg (60, 80, 120 mg) did not result in further significant increases in median gastric pH. The effects of pantoprazole on median pH from one double-blind crossover study are shown as follows. (See Table 1.)

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Serum Gastrin Effects: Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of erosive esophagitis (EE) in which 682 patients with gastroesophageal reflux disease (GERD) received 10, 20, or 40 mg of pantoprazole sodium delayed release enteric coated tablets for up to 8 weeks. At 4 weeks of treatment there was an increase in mean gastrin levels of 7%, 35%, and 72% over pretreatment values in the 10, 20, and 40 mg treatment groups, respectively. A similar increase in serum gastrin levels was noted at the 8 week visit with mean increases of 3%, 26%, and 84% for the three pantoprazole dose groups. Median serum gastrin levels remained within normal limits during maintenance therapy with pantoprazole sodium delayed-release enteric coated tablets.
In long-term international studies involving over 800 patients, a 2- to 3-fold mean increase from the pretreatment fasting serum gastrin level was observed in the initial months of the treatment with pantoprazole at doses of 40 mg per day during GERD maintenance studies and 40 mg or higher per day in patients with refractory GERD. Fasting serum gastrin levels generally remained at approximately 2 to 3 times baseline for up to 4 years of periodic follow-up in clinical trials.
Following healing of gastric or duodenal ulcers with pantoprazole treatment, elevated gastrin levels return to normal by at least 3 months.
Enterochromaffin Like Cell Effects: In 39 patients treated with oral pantoprazole 40 mg to 240 mg daily (majority receiving 40 mg to 80 mg) for up to 5 years. There was a moderate increase in ECL-cell density starting after the first year of use which appeared to plateau after 4 years. In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL-cell proliferation and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes the species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by proton pump inhibitors. However, there were no observed elevations in serum gastrin following the administration of pantoprazole at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes were observed in 1 female rat following 12 months of dosing with pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery (see Carcinogenesis, Mutagenesis, Impairment of Fertility).
Other Effects: No clinically relevant effects of pantoprazole on cardiovascular, respiratory, ophthalmic, or central nervous system function have been detected in a clinical pharmacology study, pantoprazole 40 mg given once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), thyroid-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin and growth hormone. In a 1-year study of GERD patients treated with pantoprazole 40 mg or 20 mg, there were no changes from baseline in overall levels of T3, T4, and TSH.
Clinical Studies: Pantoprazole delayed-release enteric-coated tablets were used in all clinical trials.
Erosive esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD): A U.S. multicenter double-blind, placebo-controlled study of pantoprazole sodium delayed release 10 mg, 20 mg, or 40 mg tablets, once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE or grade 3 and 10% had grade 4. The percentages of patients healed (per protocol, n=541) in this study were as follows: See Table 2.

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In the study, all pantoprazole sodium delayed release tablets treatment groups had significantly greater healing than the placebo group. This was true regardless of H. pylori status for the 40-mg and 20-mg pantoprazole sodium delayed release tablets treatment groups. The 40-mg dose of pantoprazole sodium delayed release tablet resulted in healing rates significantly greater than those found with either the 20- or 10-mg dose.
A significantly greater proportion of patients taking pantoprazole sodium delayed release 40 mg tablet experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation starting from the first day of treatment compared with placebo. Patients taking pantoprazole sodium delayed release tablets consumed significantly fewer antacid tablets per day than those taking placebo.
Pantoprazole sodium delayed release tablets 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a U.S. multicenter, double-blind study of 243 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above. The percentages of patients healed (per protocol, n=212) were as follows: See Table 3.

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Once daily treatment with pantoprazole sodium delayed-release 40 mg or 20 mg tablets resulted in significantly superior rates of healing at both 4 and 8 weeks compared twice daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori status.
A significantly greater proportion of the patients in the pantoprazole sodium delayed-release tablets treatment groups experienced complete relief of nighttime heartburn and regurgitation starting on the first day and of daytime heartburn on the second day compared with those taking nizatidine 150 mg twice daily. Patients taking pantoprazole sodium delayed release tablets consumed significantly fewer antacid tablets per day than those taking nizatidine.
Long-Term Maintenance of Healing of Erosive Esophagitis: Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in GERD patients with endoscopically-confirmed healed erosive esophagitis to demonstrate efficacy of pantoprazole sodium delayed-release tablets in long-term maintenance of healing. The two U.S. studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of pantoprazole sodium delayed-release tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in the following table, pantoprazole sodium delayed-release 40 mg and 20 mg tablets were significantly superior to ranitidine at any time point with respect to the maintenance of healing. In addition pantoprazole sodium delayed-release 40 mg tablet was superior to all other treatments studied. (See Table 4.)

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Pantoprazole sodium delayed release tablet 40 mg tablet was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. Pantoprazole sodium delayed release 20 mg tablet, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial. (See Table 5.)

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Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome: In a multicenter, open-label trial 35 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome with or without multiple endocrine neoplasia-type I, pantoprazole sodium delayed-release tablets successfully controlled gastric acid secretion. Doses ranging from 80 mg daily to 240 mg daily maintained gastric acid output below 5 mEq/h in patients with prior acid-reducing surgery. Doses were initially titrated to the individual patient needs, and adjusted in some patients based on the clinical response with lime period. Pantoprazole sodium delayed-release tablets were well-tolerated at these dose levels for prolonged periods (greater than 2 years in some patients period).
Pharmacokinetics: Pantoprazole sodium delayed-release tablets are prepared as enteric-coated tablets so that absorption of pantoprazole begins only after the label leaves the stomach. Peak serum concentration (C_max) and area under the serum concentration time curve (AUC) increase in a manner proportional to oral and intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers (see Metabolism as follows) with normal liver function receiving an oral dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (C_max) is 2.5 μg/mL, the time to reach the peak concentration (t_max) is 2.5 h and the total area under the plasma concentration versus time curve (AUC) is 4.8 μg.hr/mL. When pantoprazole is given with food its (t_max) is highly variable and may increase significantly. Following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6-14.0 L/hand it is apparent volume of distribution is 11.0-23.6 L.
Absorption: The absorption of pantoprazole is rapid with a C_max of 2.5 μg/mL that occurs approximately 2.5 hours after single or multiple oral 40-mg doses. Pantoprazole is well absorbed, it undergoes little first-pass metabolism resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of pantoprazole with food may delay its absorption up to 2 hours or longer. However, the C_max and the extent of pantoprazole absorption (AUC) are not altered. Thus, pantoprazole may be taken without regard to timing of meals.
Distribution: The apparent volume of distribution of pantoprazole is approximately 11.0-23.6 L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.
Metabolism: Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation, other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (eg. 3% of Caucasians and African-Americans and 17%-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation (≤23%) with once daily dosing.
Elimination: Metabolizes are excreted mainly (about 80%) in the urine, with the remainder being excreted in bile. The terminal elimination half-life is about 1 hour, and is prolonged in hepatic impairment; the half-life in patients with cirrhosis was 3 to 6 hours.
Special Populations: Geriatric: Only slight to moderate increases in pantoprazole AUC (43%) and C_max (26%) were found in elderly volunteers (64 to 76 years of age) after repeated oral administration, compared with younger subjects. No dosage adjustment is recommended based on age.
Pediatric: The pharmacokinetics of pantoprazole have not been investigated in patients <18 years of age.
Gender: There is a modest increase in pantoprazole AUC and C_max in women compared to men. However, weight-normalized clearance values are similar in women and men. No dosage adjustment is needed based on gender (see Use in Women under Precautions).
Renal Impairment: Most studies have not found the pharmacokinetics of pantoprazole to be altered in patients with renal impairment and licensed drug information in the UK and US generally does not recommend dosage adjustment in this group; however some UK sources, including the BNF, suggest that a maximum dose of 40 mg daily should be observed.
Hepatic Impairment: Dosage of pantoprazole may need to be reduced in severe hepatic impairment, or doses given only on alternate days. A maximum dose of 20 mg daily or 40 mg on alternate days have been suggested.
Toxicology: Carcinogenicity/Mutagenicity/Impairment of Fertility: In a 24-month carcinogenicity study, Sprague-Dawley rats were treated orally with doses of 0.5 to 200 mg/kg/day about 0.1 to 40 times the exposure on a body surface area basis of a 50-kg person closed at 40 mg/day. In the gastric fundus, treatment at 0.5 to 200 mg/kg/day (about 10 and 40 times the recommended human dose on a body surface area basis) produced benign squamous cell carcinomas. Rare gastrointestinal tumors associated with pantoprazole treatment included an adrenocarcinoma of the duodenum at 50 mg/kg/day, and benign polyps and adrenocarcinomas of the gastric fundus at 200 mg/kg/day. In the liver, treatment at 0.5 to 200 mg/kg/day produced dose-related increases in the incidences of hepatocellular adenomas and carcinomas. In the thyroid gland, treatment at 200 mg/kg/day produced increased incidences of follicular cell adrenomas and carcinomas for both male and female rats.
Sporadic occurrences of hepatocellular adenomas and a hepatocellular carcinoma were observed in Sprague-Dawley rats exposed to pantoprazole in 6-month and 12-month toxicity studies.
In a 24-month carcinogenicity study, Fischer 344 rats were treated orally with doses of 5 to 50 mg/kg/day, approximately 1 to 10 times the recommended human dose based on body surface area in the gastric fundus, treatment at 5 to 50 mg/kg/day produced enterochromaffin-like (ECL) cell hyperplasia and benign and malignant neuroendocrine cell tumors. Dose selection for this study may not have been adequate to comprehensively evaluate the carcinogenic potential of pantoprazole.
In a 24-month carcinogenicity study, B8C3F1 mice were treated orally with doses of 5 to 150 mg/kg/day, 0.5 to 15 times the recommended human dose based on body surface area. In the liver, treatment at 150 mg/kg/day produced increase incidences of hepatocellular adenomas and carcinomas in female mice. Treatment at 5 to 150 mg/kg/day also produced gastric fundic (ECL) cell hyperplasia.
A 26-week p53*/transgenic mouse carcinogenicity study was not positive. Pantoprazole was positive in the in vitro human lymphocyte chromosomal aberration assays, in one of two mouse micronucleus tests for clastogenic effects and in the in vitro Chinese hamster ovarian cell/HGPRT forward mutation assay for mutagenic effects. Equivocal results were observed in the in vivo rat liver DNA covalent binding assay. Pantoprazole was negative in the in vitro Ames mutation assay, the in vitro unscheduled DNA synthesis (UDS) assay with rat hepatocytes, the in vitro AS52/GPT mammalian cell-forward gene mutation assay, the in vitro thymidine kinase mutation test with mouse lymphoma L5178Y cells, and in the in vivo rat bone marrow cell chromosomal aberration assay.
Pantoprazole at oral doses up to 500 mg/kg/day in male rats (98 times the recommended human dose based on body surface area) and 450 mg/kg/day in female rats (88 times the recommended human dose based on body surface area) was found to have no effect on fertility and reproductive performance.