CLINICAL PHARMACOLOGY
Pharmacokinetics
Pantoprazole peak serum concentration (Cmax) and area under the serum concentration-time curve (AUC) increase in a manner proportional to intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following the administration of PROTONIX I.V. for Injection, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers (see CLINICAL PHARMACOLOGY, Metabolism) with normal liver function receiving a 40 mg dose of PROTONIX I.V. for Injection by constant rate over 15 minutes, the peak concentration (Cmax) is 5.52 μg/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 μg · hr/mL. The total clearance is 7.6-14.0 L/h and the apparent volume of distribution is 11.0-23.6 L.
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 (e.g., 3% of Caucasians and African-Americans and 17-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values from 3.5 to 10.0 hours, they still have minimal accumulation (≤23%) with once daily dosing.
Elimination
After administration of a single intravenous dose of 14C-labeled pantoprazole to healthy, normal metabolizer subjects, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole.
Special Populations
Geriatric
After repeated I.V. administration in elderly subjects (65 to 76 years of age), pantoprazole AUC and elimination half-life values were similar to those observed in 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
After oral administration there is a modest increase in pantoprazole AUC and Cmax in women compared to men. However, weight-normalized clearance values are similar in women and men. No dosage adjustment is warranted based on gender (also see Use in Women).
Renal Impairment
In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis.
Hepatic Impairment
Oral administration studies (absolute bioavailability is approximately 70%) were performed in patients with mild to severe hepatic impairment. Maximum pantoprazole concentrations increased only slightly (1.5-fold) relative to healthy subjects. Although serum elimination half-life values increased to 7-9 hours and AUC values increased by 5- to 7-fold in hepatic-impaired patients, these increases were no greater than those observed in slow CYP2C19 metabolizers, where no dosage adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once daily multiple-dose administration equal to or less than 21%. No dosage adjustment is needed in patients with mild to severe hepatic impairment. Doses higher than 40 mg/day have not been studied in hepatically-impaired patients.
Drug-Drug Interactions
Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6 and 2C9. In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4 substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam, and clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and piroxicam (CYP2C9 substrates) and theophylline (a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered. It is, therefore, expected that other drugs metabolized by CYPs 2C19, 3A4, 2D6, 2C9 and 1A2 would not significantly affect the pharmacokinetics of pantoprazole. In vivo studies also suggest that pantoprazole does not significantly affect the kinetics of other drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam and oral contraceptives [levonorgestrel/ethinyl estradiol]) metabolized by CYPs 2C19, 3A4, 2D6, 2C9 and 1A2. Therefore, it is expected that pantoprazole would not significantly affect the pharmacokinetics of other drugs metabolized by these isozymes. Dosage adjustment of such drugs is not necessary when they are co-administered with pantoprazole. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole. Although no significant drug-drug interactions have been observed in clinical studies, the potential for significant drug-drug interactions with more than once daily dosing with high doses of pantoprazole has not been studied in poor metabolizers or individuals who are hepatically impaired.
Pharmacodynamics
Mechanism of Action
Pantoprazole is a proton pump inhibitor (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.
Antisecretory Activity
The magnitude and time course for inhibition of pentagastrin-stimulated acid output (PSAO) by single doses (20 to 120 mg) of PROTONIX I.V. for Injection were assessed in a single-dose, open-label, placebo-controlled, dose-response study. The results of this study are shown in the table below. Healthy subjects received a continuous infusion for 25 hours of pentagastrin (PG) at 1 μg/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. PROTONIX I.V. for Injection had an onset of antisecretory activity within 15 to 30 minutes of administration. Doses of 20 to 80 mg of PROTONIX I.V. for Injection 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 PROTONIX I.V. for Injection was 24 hours.
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 PROTONIX I.V. for Injectionb in Healthy Subjects | ------2 hours------ | ------4 hours------ | ------12 hours------ | ------24 hours------ |
| Treatment Dose | Acid Output | %
Inhibition | Acid Output | %
Inhibition | Acid Output | %
Inhibition | Acid Output | %
Inhibition |
|
a: Compared to individual subject baseline prior to treatment with PROTONIX I.V. for Injection. NA = not applicable.
b: Inhibition of gastric acid output and the percent inhibition of stimulated acid output in response to PROTONIX I.V. for Injection may be higher after repeated doses.
|
0 mg
(Placebo,
n=4) | 39 ± 21 | NA | 26 ±14 | NA | 32 ± 20 | NA | 38 ± 24 | NA |
20mg
(n=4-6) | 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 was administered orally (40 mg enteric coated tablets) or intravenously (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 3-4 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 erosive esophagitis, 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 PROTONIX I.V. for Injection in patients with Zollinger-Ellison 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 on ECL cells.
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 this 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 was 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 PRECAUTIONS, 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 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.
Clinical Studies
Gastroesophageal Reflux Disease (GERD) Associated With a History of Erosive Esophagitis
A multicenter, double-blind, two-period placebo-controlled study was conducted to assess the ability of PROTONIX® I.V. (pantoprazole sodium) for Injection to maintain gastric acid suppression in patients switched from the oral dosage form of pantoprazole to the intravenous dosage form. Gastroesophageal reflux disease (GERD) patients (n=65, 26 to 64 years; 35 female; 9 black, 11 Hispanic, 44 white, 1 other) with a history of erosive esophagitis were randomized to receive either 20 or 40 mg of oral pantoprazole once per day for 10 days (period 1) and, then were switched in period 2 to either daily intravenous pantoprazole or placebo for 7 days, matching their respective dose level from period 1. Patients were administered all test medication with a light meal. Maximum acid output (MAO) and basal acid output (BAO) were determined 24 hours following the last day of oral medication (day 10), the first day (day 1) of intravenous administration and the last day of intravenous administration (day 7). MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 μg/kg of pentagastrin.
This study demonstrated that, after 10 days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of PROTONIX 40 mg are similar in their ability to suppress MAO and BAO in patients with GERD and a history of erosive esophagitis (see table below). Also, patients on oral PROTONIX who were switched to intravenous placebo experienced a significant increase in acid output within 48 hours of their last oral dose. However, at 48 hours after their last oral dose, patients treated with PROTONIX I.V. for Injection had a significantly lower mean basal acid output than those treated with placebo.
ANTISECRETORY EFFECTS (mEq/h) OF 40 mg PROTONIX I.V. for INJECTION AND 40 mg ORAL PROTONIX IN GERD PATIENTS WITH A HISTORY OF EROSIVE ESOPHAGITIS | Parameter | PROTONIX Delayed-Release Tablets | PROTONIX I.V.
for Injection | Placebo I.V. |
| DAY 10 | DAY 7 | DAY 7 |
|
*P< 0.0001 Significantly different from PROTONIX I.V. for Injection.
|
| Mean maximum acid output | 6.49
n=30 | 6.62
n=23 | 29.19*
n=7 |
| Mean basal acid output | 0.80
n=30 | 0.53
n=23 | 4.14*
n=7 |
To evaluate the effectiveness of PROTONIX I.V. (pantoprazole sodium) for Injection as an initial treatment to suppress gastric acid secretion, two studies were conducted.
Study 1 was a multicenter, double-blind, placebo controlled, study of the pharmacodynamic effects of PROTONIX I.V. for Injection and oral PROTONIX. Patients with GERD and a history of erosive esophagitis (n=78, 20-67 years; 39 females; 7 black, 19 Hispanic, 52 white) were randomized to receive either 40 mg intravenous pantoprazole, 40 mg oral pantoprazole, or placebo once daily for 7 days. Following an overnight fast, test medication was administered and patients were given a light meal within 15 minutes. MAO and BAO were determined 24 hours following the last day of study medication. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 μg/kg of pentagastrin to stimulate acid secretion. This study demonstrated that, after treatment for 7 days, patients treated with PROTONIX I.V. for Injection had a significantly lower MAO and BAO than those treated with placebo (p <0.001), and results were comparable to those of patients treated with oral PROTONIX (see table below).
ANTISECRETORY EFFECTS (mEq/h) OF INITIAL TREATMENT WITH 40 mg PROTONIX I.V. for INJECTION AND 40 mg ORAL PROTONIX IN GERD PATIENTS WITH A HISTORY OF EROSIVE ESOPHAGITIS | Parameter | PROTONIX I.V.
for Injection | PROTONIX Delayed-Release Tablets | Placebo |
| DAY 7 | DAY 7 | DAY 7 |
|
*P< 0.001 Significantly different from PROTONIX I.V. for Injection.
|
| Maximum acid output (mean ± SD) | 8.4 ± 5.9
n=25 | 6.3 ± 6.6
n=22 | 20.9 ± 14.5*
n=24 |
| Basal acid output (mean ± SD) | 0.4± 0.5
n=25 | 0.6 ± 0.8
n=22 | 2.8 ± 3.0*
n=23 |
Study 2 was a single-center, double-blind, parallel-group study to compare the clinical effects of PROTONIX I.V. for Injection and oral PROTONIX. Patients (n=45, median age 56 years, 21 males and 24 females) with acute endoscopically proven reflux esophagitis (Savary/Miller Stage II or III) with at least 1 of 3 symptoms typical for reflux esophagitis (acid eructation, heartburn, or pain on swallowing) were randomized to receive either 40 mg intravenous pantoprazole or 40 mg oral pantoprazole daily for 5 days. After the initial 5 days, all patients were treated with 40 mg oral pantoprazole daily to complete a total of 8 weeks of treatment. Symptom relief was assessed by calculating the daily mean of the sums of the average scores for these 3 symptoms and the daily mean of the average score for each of the symptoms separately. There was no significant difference in symptom relief between PROTONIX I.V. and oral PROTONIX therapy within the first 5 days. A repeat endoscopy after 8 weeks of treatment revealed that 20 out of 23 (87%) of the PROTONIX I.V. plus oral PROTONIX patients and 19 out of 22 (86%) of the oral PROTONIX patients had endoscopically proven healing of their esophageal lesions.
Data comparing PROTONIX I.V. for Injection to other proton pump inhibitors (oral or I.V.) or H2 receptor antagonists (oral or I.V.) are limited, and therefore, are inadequate to support any conclusions regarding comparative efficacy.
Pathological Hypersecretion Associated with Zollinger-Ellison Syndrome
Two studies measured the pharmacodynamic effects of 6 day treatment with PROTONIX I.V. for Injection in patients with Zollinger-Ellison Syndrome (with and without multiple endocrine neoplasia type I). In one of these studies, an initial treatment with PROTONIX I.V. for Injection in 21 patients (29 to 75 years; 8 female; 4 black, 1 Hispanic, 16 white) reduced acid output to the target level (≤ 10 mEq/h) and significantly reduced H+ concentration and the volume of gastric secretions; target levels were achieved within 45 minutes of drug administration.
In the other study of 14 patients (38 to 67 years; 5 female; 2 black, 12 white) with Zollinger-Ellison Syndrome, treatment was switched from an oral proton pump inhibitor to PROTONIX I.V. for Injection. PROTONIX I.V. for Injection maintained or improved control of gastric acid secretion.
In both studies, PROTONIX I.V. for Injection 160 or 240 mg per day in divided doses maintained basal acid secretion below target levels in all patients. Target levels were 10 mEq/h in patients without prior gastric surgery, and 5 mEq/h in all patients with prior gastric acid-reducing surgery. Once gastric acid secretion was controlled, there was no evidence of tolerance during this 7 day study. Basal acid secretion was maintained below target levels for at least 24 hours in all patients and through the end of treatment in these studies (3 to 7 days) in all but 1 patient who required a dose adjustment guided by acid output measurements until acid control was achieved. In both studies, doses were adjusted to the individual patient need, but gastric acid secretion was controlled in greater than 80% of patients by a starting regimen of 80 mg q12h.
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