Pantoprazole Sodium (Page 5 of 8)

11 DESCRIPTION

The active ingredient in pantoprazole sodium for injection (pantoprazole sodium), a PPI, is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H -benzimidazole, a compound that inhibits gastric acid secretion. Its molecular formula is C16 H14 F2 N3 NaO4 S, with a molecular weight of 405.4. The structural formula is:

Pantoprazole Sodium Chemical Structure
(click image for full-size original)

Pantoprazole sodium USP is a white to off-white powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases with decreasing pH. The reconstituted solution of pantoprazole sodium for injection is in the pH range 9.0 to 10.5. Pantoprazole sodium for injection is supplied for intravenous administration as a sterile, freeze-dried, white to off-white, porous cake or powder in a single-dose clear glass vial fitted with a rubber stopper and crimp seal. Each vial contains 40 mg pantoprazole (equivalent to 45.1 mg of pantoprazole sodium USP), edetate disodium (1 mg), and sodium hydroxide to adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Pantoprazole is a PPI that suppresses the final step in gastric acid production by covalently binding to the (H+ , K+)-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 (H+ , K+)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested (20 mg to 120 mg).

12.2 Pharmacodynamics

Antisecretory Activity
The magnitude and time course for inhibition of pentagastrin-stimulated acid output (PSAO) by single doses (20 to 120 mg) of pantoprazole sodium were assessed in a single-dose, open-label, placebo-controlled, dose-response study. The results of this study are shown in Table 3. Healthy subjects received a continuous infusion for 25 hours of pentagastrin (PG) at 1 mcg/kg/h, a dose known to produce submaximal gastric acid secretion. The placebo group showed a sustained, continuous acid output for 25 hours, validating the reliability of the testing model. Pantoprazole sodium had an onset of antisecretory activity within 15 to 30 minutes of administration. Doses of 20 to 80 mg of pantoprazole sodium substantially reduced the 24-hour cumulative PSAO in a dose-dependent manner, despite a short plasma elimination half-life. Complete suppression of PSAO was achieved with 80 mg within approximately 2 hours and no further significant suppression was seen with 120 mg. The duration of action of pantoprazole sodium was 24 hours.

Table 3: Gastric Acid Output (mEq/hr, Mean ± SD) and Percent Inhibitiona (Mean ± SD) of Pentagastrin-Stimulated Acid Output Over 24 Hours Following a Single Dose of Pantoprazole Sodiumb in Healthy Subjects
a: Compared to individual subject baseline prior to treatment with pantoprazole sodium. NA = not applicable. b: Inhibition of gastric acid output and the percent inhibition of stimulated acid output in response to pantoprazole sodium may be higher after repeated doses.
——2 hours—–­ ——4 hours—–­ ——12 hours—– ——24 hours—–
Treatment Dose Acid Output % Inhibition Acid Output % Inhibition Acid Output % Inhibition Acid Output % Inhibition
0 mg (Placebo, n=4) 39 ± 21 NA 26 ± 14 NA 32 ± 20 NA 38 ± 24 NA
20 mg (n=4 to 6) 13 ± 18 47 ± 27 6 ± 8 83 ± 21 20 ± 20 54 ± 44 30 ± 23 45 ± 43
40 mg (n=8) 5 ± 5 82 ± 11 4 ± 4 90 ± 11 11 ± 10 81 ± 13 16 ± 12 52 ± 36
80 mg (n=8) 0.1 ± 0.2 96 ± 6 0.3 ± 0.4 99 ± 1 2 ± 2 90 ± 7 7 ± 4 63 ± 18

In one study of gastric pH in healthy subjects, pantoprazole sodium was administered orally (40 mg enteric coated tablets) or pantoprazole sodium for injection (40 mg) once daily for 5 days and pH was measured for 24 hours following the fifth dose. The outcome measure was median percent of time that pH was ≥ 4 and the results were similar for intravenous and oral medications; however, the clinical significance of this parameter is unknown.
Serum Gastrin Effects
Serum gastrin concentrations were assessed in two placebo-controlled studies.
In a 5-day study of oral pantoprazole with 40 and 60 mg doses in healthy subjects, following the last dose on day 5, median 24-hour serum gastrin concentrations were elevated by 3- to 4- fold compared to placebo in both 40 and 60 mg dose groups. However, by 24 hours following the last dose, median serum gastrin concentrations for both groups returned to normal levels.
In another placebo-controlled, 7-day study of 40 mg intravenous or oral pantoprazole in patients with GERD and a history of EE, the mean serum gastrin concentration increased approximately 50% from baseline and as compared with placebo, but remained within the normal range.
During 6 days of repeated administration of pantoprazole sodium in patients with ZE Syndrome, consistent changes of serum gastrin concentrations from baseline were not observed.
Enterochromaffin-Like (ECL) Cell Effects
There are no data available on the effects of intravenous pantoprazole sodium on ECL cells.
In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to oral 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 this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by PPIs. However, there were no observed elevations in serum gastrin following the administration of oral 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 was observed in 1 female rat following 12 months of dosing with oral pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery [see Nonclinical Toxicology (13.1)].

Endocrine Effects

In a clinical pharmacology study, pantoprazole 40 mg given orally once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T3 ), thyroxine (T4 ), thyroid-stimulating hormone, thyronine-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.

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