Abbott-Pantoprazole - Scientific Information
|Condition:||Barrett's Esophagus, Duodenal Ulcer, Erosive Esophagitis, Gastritis (Gastritis/Duodenitis), GERD, Helicobacter Pylori Infection, Peptic Ulcer, Stress Ulcer Prophylaxis, Stomach Ulcer (Gastric Ulcer), Zollinger-Ellison Syndrome|
|Class:||Proton pump inhibitors|
|Proper name:||Pantoprazole sodium sesquihydrate|
|Chemical name:||Sodium5-(difluoromethoxy) -2- [(RS) -[(3,4-dimethoxy pyridin-2-yl) methyl] sulphinyl] benzimidazol -1-ide sesquihydrate.|
|Molecular formula and:||C16H14F2N3NaO4S × 1.5 H2O|
|Molecular mass:||432.4 g/mol|
Physical description: White or almost white powder
Solubilities in common solvents (e.g., water, alcohols, chloroform, acetone, dilute acids, etc.): Pantoprazole sodium is freely soluble in ethanol and water, and practically insoluble in hexane.
Comparative Bioavailability Studies
A double-blind, randomised, two-period, two -treatment, two-sequence, single-dose, crossover bioequivalence study comparing a 1 x 40 mg dose of Abbott-Pantoprazole (Pantoprazole Sodium Delayed Release Tablets) of Abbott Laboratories, Limited, with a 1 x 40 mg dose of Pantoloc (Pantoprazole Sodium Enteric-Coated Tablets) of Nycomed Canada Inc., in 51 healthy, adult, Asian male subjects under fed conditions. A summary of the bioavailability data is presented in Table 1.
|Pantoprazole (1 x 40 mg) From measured data Geometric Mean Arithmetic Mean (CV%)|
|Parameter||Test*||Reference†||% Ratio of Geometric Means||90% Confidence Interval|
|AUCT (ng.hr/mL)||5024.07 6978.01 (105.5)||4875.37 7228.38 (113.0)||103.16||94.74-112.34|
|AUCI (ng.hr/mL)||5106.85 7218.56 (111.2)||4983.47 7591.05 (121.8)||102.58||94.58-111.26|
|Cmax (ng/mL)||2726.78 2896.64 (31.6)||2637.19 2963.91 (39.2)||103.58||92.74-115.68|
|Tmax§ (hr)||5.50 (3.00 - 16.00)||5.50 (3.50 - 16.00)|
|T1⁄2 (hr)||1.83 (117.4)||2.01 (135.9)|
* Abbott-Pantoprazole 40 mg Delayed Release Tablets
† Pantoloc 40 mg Enteric-Coated Tablets by Nycomed Canada Inc., purchased in Canada.
§ Expressed as the median (range) only
1⁄2 Expressed as the arithmetic mean (CV%) only
A double-blind, randomised, two-period, two -treatment, two-sequence, single-dose, crossover bioequivalence study comparing a 1 x 40 mg dose of Abbott-Pantoprazole (Pantoprazole Sodium Delayed Release Tablets) of Abbott Laboratories, Limited, with a 1 x 40 mg dose of Pantoloc® (Pantoprazole Sodium Enteric-Coated Tablets) of Nycomed Canada Inc., in 37 healthy, adult, Asian male subjects under fasting conditions. A summary of the bioavailability data is presented in Table 2.
|Pantoprazole (1 x 40 mg) From measured data Geometric Mean Arithmetic Mean (CV%)|
|Parameter||Test*||Reference†||% Ratio of Geometric Means||90% Confidence Interval|
|AUCT (ng.hr/mL)||6949.82 10468.48 (104.4)||7322.39 10670.28 (102.1)||95.13||88.84-101.87|
|AUCI (ng.hr/mL)||7116.44 10898.09 (108.0)||7456.24 11001.13 (105.2)||95.65||89.55-102.16|
|Cmax (ng/mL)||2894.54 3156.71 (38.6)||3254.09 3417.73 (31.2)||89.20||80.00-99.46|
|Tmax§ (h)||2.67 (1.33-8.00)||2.33 (1.33-4.67)|
|T1⁄2 (h)||2.53 (121.8)||2.42 (108.4)|
Symptomatic Gastro-Esophageal Reflux Disease
In a US placebo-controlled study involving 538 patients, a significantly greater proportion of patients taking pantoprazole sodium 40 mg 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 consumed significantly fewer antacid tablets per day than those taking placebo.
In a second US study involving 215 patients, a significantly greater proportion of the patients in the pantoprazole sodium 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 consumed significantly fewer antacid tablets per day than those taking nizatidine.
Prevention of Gastrointestinal Lesions Induced by Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Two pivotal studies have been conducted to investigate the effect of pantoprazole sodium in the prevention of the occurrence of endoscopically evident gastrointestinal lesions in patients who, at the start of the study do not present with endoscopically evident gastrointestinal lesions but who have increased risk to develop NSAID-associated upper gastrointestinal lesions.
The following efficacy criteria were used in the studies:
- Therapeutic failure – Defined as “detection of peptic ulcer and/or more than ten erosions and/or petechiae in the stomach or duodenum, and/or, reflux esophagitis, and/or, adverse event (assessed as 'likely' or 'definitely' related to the study medication), and/or gastrointestinal symptoms leading to premature termination”.
- Endoscopic failure – Defined as “detection of peptic ulcer, and/or, more than ten erosions/petechiae in the stomach or duodenum, and/or, reflux esophagitis”.
- Symptomatic failure – Defined as the occurrence of severe gastrointestinal symptoms such as heartburn, epigastric pain, retrosternal feeling of tightness, abdominal pain, eructation of air, acid eructation, pain on swallowing, nausea, retching, vomiting (often collectively referred to as dyspeptic symptoms) including at least “likely” related adverse events of severe intensity concerning the gastrointestinal tract.
The results of the studies in patients who require continuous intake of NSAIDs and who have increased risk to develop NSAID-associated gastrointestinal lesions are presented in the table below.
|In remission with regard to Efficacy Criteria:||Time interval (months)||Study 1; Pantoprazole 20 mg od (P20) vs pantoprazole 40 mg od (P40) vs omeprazole 20 mg od (O20)||Study 2; Pantoprazole 20 mg od (P20) vs misoprostol 200 μg bid (M200)|
|Remission Rate (%)||Remission Rate (%)|
|P20 n = 196||P40 n = 199||O20 n = 200||P20 n = 257||M200 n = 258||p value P20 vs M200|
“In remission” is defined as patients who did not have any of the findings (e.g. “therapeutic failure”, “endoscopic failure”, or symptomatic failure” after 6 months).
Remission rates were obtained by subtracting failures from 100%.
In a six-month study involving 595 patients requiring continuous intake of NSAIDs, treatment with pantoprazole 20 mg od was equivalent to the treatment with pantoprazole 40 mg od and omeprazole 20 mg od in this indication.
In a second six-month study involving 515 patients requiring continuous intake of NSAIDs, pantoprazole 20 mg was not only equivalent but statistically significantly superior to treatment with misoprostol 200 μg bid with respect to symptomatic and endoscopic findings.
Helicobacter Pylori Associated Duodenal Ulcer
|Treatment||Eradication Rate (ITT + kpa analysis)||95% CI||Ulcer Healing Rate after therapy cessation (MITT analysis)||95% CI|
|Pantoprazole 40 mg + clarithromycin 500 mg + metronidazole 500 mg, all twice daily for 1 week (PCM)||Study 1||83%||75-90%||88%||80-93%|
|Study 2||96%||91-98%||Not assessed|
|Pantoprazole 40 mg + amoxicillin 1000 mg + clarithromycin 500 mg, all twice daily for 1 week (PAC)||Study 2||93%||88-97%||Not assessed|
ITT + kpa: Patients who were H. pylori positive at the initial examination and had complete and valid results for the requisite (based on the study) number of tests at the appropriate follow-up visit. In study 1, 3 of 4 H. pylori tests must be complete and valid. Study 1: Patients with active duodenal ulcer, were assessed for H. pylori status by UBT, histology, culture and rapid urease, n=213 (ITT + kpa) ; Study 2: Patients with active duodenal ulcer, were assessed for H. pylori status by UBT and rapid urease pre-treatment and by UBT post-treatment, n=283 (ITT + kpa) ; Study 3: Patients with active duodenal ulcer, were assessed for H. pylori status by rapid urease and UBT pre-treatment and by UBT and histology post- treatment, n=62 (ITT + kpa); Study 4: Patients with active duodenal ulcer, were assessed for H. pylori status by rapid urease, culture and histology pre-treatment and culture and histology post-treatment, n=57 (ITT + kpa)
Prevention of Relapse of Reflux Esophagitis
The long-term maintenance of healing of erosive esophagitis was assessed in two U.S. randomised, double -blind, parallel-group, active controlled studies. Eligible patients in both studies had a recent history of grade II or III (Hetzel-Dent) erosive esophagitis, and endoscopically demonstrated healing. Both studies used as the primary endpoint endoscopically demonstrated recurrence (assessed at month 1, 3, 6 and 12) of erosive esophagitis ('relapse'). Gelusil antacid tablets were to be taken as needed for symptomatic relief after 5 or more minutes of retrosternal pain, acid regurgitation, or dysphagia, but not within 1 hour before or after taking study medication. Ad hoc endoscopies were performed when symptoms of GERD occurred for more than 3 consecutive days. As the primary analysis Kaplan Meier’s method was performed, whereas the discrete analysis was secondary. In the U.S. studies, there were a limited number of H. pylori positive patients. Results for this sub-group are therefore qualitative only.
In the US studies, the results of Kaplan-Meier’s analyses showed that the cumulative proportion of relapse over time was dose-related for the pantoprazole treatment groups. The cumulative proportion of relapse at 12 months for patients treated with pantoprazole 20 mg and pantoprazole 40 mg exhibited a statistically significant difference in the pooled data (p-value=0.001) and in the data of one of the studies (3001A1-302-US: p-value =0.012, 3001A1-303-US p-value=0.052) (p-values adjusted for pairwise comparison).
In the discrete analysis of the pooled results of the two U.S. studies, 40 mg was significantly (p- value=0.004) more effective in the maintenance of healed erosive esophagitis compared to 20 mg (see following table).
|Pantoprazole 20 mg n/N(%)||Pantoprazole 40 mg n/N(%)||Ranitidine 150 mg n/N(%)|
|Month 12||25/75(33.3)*||10/64(15.6)* a||52/76(68.4)|
|Month 12||50/148 (33.8) *||25/142 (17.6) * a||104/154 (67.5)|
* Statistically significant between treatment and ranitidine at 0.05 level;
a Statistically significant between pantoprazole 40 mg and 20 mg with adjusted p-value (Holm procedure).
Mean age 302-US 49.2 years, 303-US 48.95 years, 302-US: 28% female / 72% male 303-US: 38% female / 62% male, 302 -US: 3.9 % black, 4.1 % Hispanic, <1% Asian, 91% white, <1% other, US- 303: 6.4 % black, 6.4 % Hispanic, <1% Asian, 86% white, <1% other, US-302: 85% H. pylori negative, 15% H. pylori positive, US-303: 88% H. pylori negative, 12% H. pylori positive.
Additionally, long-term maintenance of healing of erosive esophagitis was assessed in two European, randomized, double-blind, parallel- group non-inferiority studies. Eligible patients in both studies had a recent history of grade II or III (Savary-Miller) erosive esophagitis, and endoscopically demonstrated healing. Both studies used as the primary endpoint endoscopically demonstrated recurrence of erosive esophagitis ('relapse'). Pantoprazole 40 mg is non-inferior to pantoprazole 20 mg which means patients who were treated with pantoprazole 40 mg showed no less reduction in the proportion of relapse at 12 months compared to pantoprazole 20 mg.
|Study||Month||Relapse rates (%)||Diff. Between Treatment and 95%CI (%)|
|40 mg Pantoprazole||20 mg Pantoprazole|
|FK3028||12||39/174 (22)||45/174 (26)||-3.5 (-12.4;5.5)|
|FK3033||12||30/151 (20)||49/161 (30)||-10.6 (-20;-1)|
|Pooled||12||69/325 (21)||94/335 (28)||-6.8 (-13.4;-0.3)|
Mean age FK3028 56 years, FK3033 50 years, FK3028 35% female / 65% male, FK3033: 28% female / 72% male. * These studies were performed between 1993 – 1997; at that time determination of H.pylori status and eradication of H. pylori was not widely introduced.
In vivo, pantoprazole produced marked and long-lasting inhibition of basal and stimulated gastric acid secretion with median effective dose (ED50 ) values ranging from 0.2 -2.4 mg/kg in rats and dogs. In addition to the administration of single doses, pantoprazole has been tested upon repeated oral administration (e.g. during 24-h pH-metry in dogs performed under pentagastrin stimulation). While a dose of 1.2 mg/kg did not significantly elevate pH on Day 1, pH rose to values between 4 and 7 after a 5-day dosing regimen. This effect was no longer observed 18 hours after the last drug administration. In various gastric ulcer models in the rat, pantoprazole showed antiulcer activity.
In parallel to the profound inhibition of gastric acid secretion, pantoprazole induced a dose-dependent increase in serum gastrin levels up to values above 1000 pg/mL from a control level of about 100 pg/mL. As a consequence of persisting hypergastrinemia in rats after high/doses of pantoprazole, hyperplastic changes were observed in the fundic mucosa with an increased density of enterochromaffin-like (ECL) cells. These changes were reversible during drug-free recovery periods.
In a battery of standard high-dose pharmacology tests, no influence of pantoprazole was detected on the central and peripheral nervous system. In conscious dogs as well as anaesthetized cats receiving single i.v. doses up to 10 mg/kg pantoprazole, no consistent changes with respect to respiratory rate, ECG, EEG, blood pressure and heart rate were observed. Higher doses led to modest and transient reductions in blood pressure and variable changes in heart rate. No influence of pantoprazole was found on renal function and on autonomic functions, such as pancreatic and bile secretion, gastrointestinal motility and body temperature.
No consistent changes in the effects of ethanol, pentobarbitone, or hexobarbitone were induced by pantoprazole; only doses over 300 mg/kg prolonged the effects of diazepam.
Absorption and Distribution
Pantoprazole is absorbed rapidly in both rat and dog. Peak plasma levels are attained within 15 to 20 minutes in the rat and after about 1 hour in the dog. Oral bioavailability is 33% in the rat and 49% in the dog. Following absorption, autoradiography and quantitative tissue distribution experiments have shown that pantoprazole is rapidly distributed to extravascular sites. Following administration of pantoprazole, distribution of radioactivity in the blood and most organs is found to be uniform initially. After 16 hours, radiolabelled pantoprazole is predominantly detected in the stomach wall. After 48 hours, all the administered radioactivity is found to have been excreted. Penetration of the blood-brain barrier by radiolabelled pantoprazole is very low. Protein binding in the rat and dog is 95% and 86%, respectively.
Metabolism and Excretion
Pantoprazole is extensively metabolized. Oxidations and reductions at different sites of the molecule, together with Phase II reactions (sulfation and glucuronidation) and combinations thereof result in the formation of various metabolites. In rats and dogs, 29-33% of a pantoprazole dose is excreted as urinary metabolites and the remainder as biliary/fecal metabolites. Almost no parent compound can be found in the excreta.
Mammoglandular passage and transplacental transport has been investigated in the rat using radiolabelled pantoprazole. A maximum of 0.23% of the administered dose is excreted in the milk. Radioactivity penetrates the placenta with 0.1-0.2% of the dose /g fetal tissue on the first day after oral administration.
Pantoprazole is a potent inhibitor of gastric acid secretion. This was demonstrated with pantoprazole by use of a gastric acid aspiration technique as well as by continuous intragastric pH monitoring. Using the aspiration technique it was also shown that pantoprazole caused a dose-dependent reduction of secreted gastric acid volume.
|Dose||Mean %Inhibition of PSAO|
With 40 mg administered orally, effective inhibition of gastric acid secretion was achieved. Pantoprazole 40 mg was significantly superior to standard H2-blocker therapy (300 mg ranitidine at night) with regard to median 24-hour and daytime pH; however, not for nighttime measurements.
|Time of Day||Median pH|
|Placebo||Pantoprazole 40 mg||Ranitidine 300 mg|
|08.00-22.00 (Day Time)||1.8||4.4*||2.0|
|22.00-08.00 (Night Time)||1.3||3.1||3.7|
* p<0.05 vs ranitidine
Increasing the once daily dose from 40 mg to 80 mg pantoprazole did not result in a significantly higher median 24-hour pH.
|40 mg||80 mg|
Hence, once daily administration of 40 mg pantoprazole should be sufficient for the treatment of most patients with acid-related diseases.
The absolute bioavailability of the pantoprazole tablet is 77%. Maximum serum concentrations of pantoprazole are reached within approximately 2.5 hours after oral intake. Following a dose of 40 mg, mean maximum serum concentrations of approximately 2 μg/mL and 3 μg/mL are reached after 2 to 3 hours. There is no food effect on AUC (bioavailability) and Cmax. However, time to reach maximum serum concentrations is slightly increased when the drug is given together with a high caloric breakfast. Taking into account the long duration of action of pantoprazole, which by far exceeds the time period over which serum concentrations are measurable, this observed variation in tmax is considered to be of no clinical importance.
Pantoprazole is approximately 98% bound to serum protein.
Despite its relatively short elimination half-life of approximately 1 hour, the antisecretory effect increases during repeated once daily administration, demonstrating that the duration of action markedly exceeds the serum elimination half-life. This means that there is no direct correlation between the serum concentrations and the pharmacodynamic action.
Morning administration of pantoprazole was significantly superior to evening dosing with regard to 24 hour intragastric pH, hence morning dosing should be recommended for the treatment of patients. Since the intake of the drug before a breakfast did not influence Cmax and AUC, which characterize rate and extent of absorption, no specific requirements for intake of pantoprazole in relation to breakfast are necessary.
Pantoprazole undergoes metabolic transformation in the liver. Approximately 82% of the oral dose is removed by renal excretion, and the remainder via feces. The main serum metabolites (M1-M3) are sulphate conjugates formed after demethylation at the pyridine moiety, the sulphoxide group being either retained (M2, main metabolite), or oxidized to a sulphone (M1), or reduced to a sulphide (M3). These metabolites also occur in the urine (main metabolite M2). Conjugates with glucuronic acid are also found in the urine.
In single dose clinical pharmacology studies, pantoprazole was administered to fasting healthy volunteers concomitantly with combinations of amoxicillin, clarithromycin, and/or metronidazole. Pharmacokinetic characteristics of each of the subject medications administered alone were also evaluated as a reference point. Equivalence between the test (i.e., in combination regimen) and the respective reference was concluded when the 90% confidence interval was within the equivalence range of 0.67 to 1.50 for the AUC0-∞ and Cmax.
The potential influence of the concomitant administration of pantoprazole 40 mg with clarithromycin 500 mg and metronidazole 500 mg on pharmacokinetic characteristics was evaluated following a single oral dose administered to fasted healthy volunteers. A lack of interaction was shown for each of the drugs (see Table 6 below).
|AUC0-∞||1.02 (0.99, 1.06)||1.16 (1.04, 1.28)||1.11 (0.98, 1.25)|
|Cmax||1.08 (0.99, 1.14)||1.15 (0.91, 1.45)||1.21 (1.06, 1.39)|
* Ref = drug alone
Test = combination
Concomitant administration was well tolerated, with no clinically relevant changes in vital signs, ECG, or clinical laboratory parameters noted.
The potential influence of the concomitant administration of pantoprazole 40 mg with clarithromycin 500 mg and amoxicillin 1000 mg on pharmacokinetic characteristics was also evaluated following a single oral dose administered to fasted healthy volunteers. A lack of interaction was shown for each of the drugs (see Table 7 below).
|AUC0-∞||0.93 (0.85, 1.02)||1.14 (1.00, 1.31)||1.10 (1.03, 1.18)|
|Cmax||0.97 (0.86, 1.10)||1.18 (1.00, 1.40)||1.11 (0.94, 1.31)|
* Ref = drug alone
Test = combination
Concomitant administration was well tolerated, with no clinically relevant changes in vital signs, ECG, or clinical laboratory parameters noted.
In vivo Studies
Female mice were infected with Helicobacter felis on Days 1, 3, and 5 by gavage with 108 - 109 bacteria per animal. Starting on Day 8, the mice were treated three times daily with placebo or active drug (pantoprazole and/or amoxicillin, clarithromycin, tetracycline) for four days. One day after the last treatment, the mice were sacrificed and a biopsy of the antrum was subjected to a urease test, with only those tests showing a dark violet colour considered to contain urease-positive Helicobacter.
Doses of the active agents, the number of infected animals per group, and resulting elimination rates for the H. felis infection were as follows:
|Active Dosing Groups||Elimination Rates|
|Pantoprazole 100 mg/kg tid (n=10)||0%|
|Amoxicillin 0.5 mg/kg tid (n=10)||40%|
|Amoxicillin 3.0 mg/kg tid (n=10)||100%|
|Clarithromycin 0.5 mg/kg tid (n=10)||10%|
|Clarithromycin 3.0 mg/kg tid (n=10)||70%|
|Tetracycline 3.0 mg/kg tid (n=20)||55%|
|Tetracycline 15.0 mg/kg tid ( n=10)||90%|
|Pantoprazole 100 mg/kg tid + amoxicillin 0.5 mg/kg tid (n=10)||100%|
|Pantoprazole 100 mg/kg tid + clarithromycin 0.5 mg/kg tid (n=10)||90%|
|Pantoprazole 100 mg/kg tid + tetracycline 3.0 mg/kg tid (n=20)||80%|
In the infected, placebo dosed positive control group, 24 of the 25 mice had positive urease tests, while the negative control group (not infected, placebo dosed) all had negative urease tests.
Pantoprazole alone was without effect on Helicobacter pylori infection, while in combination therapy with the antibiotics; pantoprazole had a potentiating effect on the elimination rate of Helicobacter pylori infection. The results show a potentiation by a factor of about six, i.e., pantoprazole plus the low dose antibiotic achieved an infection elimination rate greater than or approximately equal to the higher dose of antibiotic given alone, which was dosed at five to six times higher than the low dose.
In acute toxicity studies in mice the mean lethal dose (LD50) values for pantoprazole were found to be around 390 mg/kg bodyweight for i.v. administration and around 700 mg/kg bodyweight for oral administration.
In the rat the corresponding values were around 250 mg/kg for i.v. administration and > 1000 mg/kg for oral administration.
Acute toxicity studies were conducted on B8810-044, the major degradation product of pantoprazole. The approximate LD50 values for mice (119-167 mg/kg) and rats (73-82 mg/kg) were lower than those for pantoprazole itself, after intravenous injection, but the toxic symptoms were similar to those noted for the drug. A 4-week repeat dose study was also conducted using this degradation product using the intravenous route in rats. Rats received 5 and 25 mg of B8810-044/kg, while a comparison group received 25 mg/kg of pantoprazole. Muscle twitches were observed immediately after injection in rats receiving 25 mg/kg of the degradation product, but not in the pantoprazole-treated animals. Otherwise the compounds were comparable.
* Doses refer to the sodium salt administered in solution
** sodium salt as dry powder in gelatine capsules
The symptoms seen after lethal oral or i.v. doses were similar in rats and mice: the animals displayed ataxia, reduced activity, hypothermia and prostration. Surviving animals recovered uneventfully. Salivation, tremor, lethargy, prostration and coma were seen in dogs at lethal oral doses, with death occurring on the following day. Ataxia, tremor and a prone position were noted at sublethal oral and i.v. doses, but the survivors recovered quickly and appeared fully normal after the 2-week observation period.
Daily oral doses of pantoprazole in 1- and 6-month SD rat repeated-dose studies were 1, 5, 20, and 500 mg/kg and 0.8, 4, 16 and 320 mg/kg, respectively; doses for a 1 month rat i.v. study were 1, 5, and 30 mg/kg.
A 12-month toxicity study in SD rats was conducted using daily oral doses of 5, 50, and 300 mg/kg. Daily oral doses in 1- and 6 month (beagle) dog studies were 7.5, 15, 30, and
100 mg/kg and 5, 15, 30, and 60 mg/kg respectively. In a 12-month oral study in dogs, 2.5, 15, and 60 mg/kg were administered daily.
Hypergastrinemia was dose-related and was observed at all doses investigated in the studies mentioned above, but was reversible upon cessation of treatment. Drug-related effects on the stomach included increased stomach weights and morphologic changes of the mucosa. In the 6-month rat study, increased stomach weight and some cellular changes were detected at all doses. In the 1-month rat study, gastric changes were detected at 5 mg/kg but not at 1 mg/kg. In dogs, increased stomach weight was observed at all doses studied. There were no gastric cellular changes detected at oral doses of 7.5 or 5 mg/kg in the 1- and 6-month dog studies, respectively. In both species, most gastric effects were reversible after a 4- or 8-week recovery period. Hypergastinemia and gastric changes were considered to be the consequence of the pharmacological action of the compound, namely prolonged and profound inhibition of acid secretion.
Increased liver weight in the rat experiments was considered to be a consequence of the induction of hepatic drug metabolizing systems and was found to be associated with centrilobular hepatocellular hypertrophy at 320 mg/kg in the 6-month study and at 50 and 300 mg/kg after 12 months of treatment. Increased liver weights were also detected at a dose of 16 mg/kg in male rats in the 6-month study and at 500 mg/kg, but not 20 mg/kg, in the 1-month study. Increased liver weight was noted in male dogs of all dose groups in the 1-month study, though only at 100 mg/kg in females on the same study. Both males and females had increased liver weights after 6 months administration of 30 or 60 mg/kg, but not of 15 mg/kg. In the 12-month study, liver weights were increased only in the female dogs dosed with 60 mg/kg. There were no hepatic lesions that correlated with increased liver weight in the dog studies. In dogs, the increase in liver weight was attributed to an activation of hepatic drug metabolizing systems as mentioned for rats.
Thyroid activation in animal experiments is due to the rapid metabolization of thyroid hormones in the liver and has been described in a similar form for other drugs. Thyroid weights were increased in both sexes at 500 mg/kg in the 1-month rat study and at 320 mg/kg in the rat 6-month study. Thyroid follicular cell hypertrophy was noted in females at these doses, in rats treated with 50 and 300 mg/kg in the 12 month study and also in a few females at 16 mg/kg in the 6 month study. There were no thyroid effects in rats at or below an oral dose of 5 mg/kg even after 1 year. In the dog, no effects were seen on the thyroid after 4 weeks. Only slight, but not dose-dependent, increases in thyroid weights were seen after 6 months, but no changes were observed histologically. In the 12 month study, the relative thyroid weights in the 60 mg/kg group were only slightly higher than those of the control dogs, and changes were detected histologically in only a few animals under 15 and 60 mg/kg. In both species, changes were reversible.
Increased serum cholesterol values were noted in all groups in the 6- and 12 month dog studies and in all groups in the 12 month rat study. The increases were slight and were reversible after cessation of treatment.
In dog studies, oral doses of pantoprazole of 15 mg/kg or above caused a transient pulmonary edema in a proportion of naive dogs during the first week of drug administration. Pulmonary edema caused death in a few dogs after repeated oral doses of 15 mg/kg or above. There is strong evidence that the pulmonary toxicity is due to a thiol metabolite which does not occur in man. No evidence of pulmonary edema was detected in dogs at an oral dose of 7.5 mg/kg nor at
60 mg/kg when administered daily for 6 or 12 months after a 1 week dose escalation phase.
In a four week oral toxicity study, Beagle dogs were given daily oral doses of encapsulated commercial products including pantoprazole, clarithromycin, metronidazole, and amoxicillin. Groups of three male and three female dogs received the following daily doses of pantoprazole and/or antibiotics:
Group 1 - pantoprazole 16 mg/kg
Group 2 - clarithromycin 75 mg/kg + metronidazole 50 mg/kg
Group 3 - pantoprazole 16 mg/kg + amoxicillin 120 mg/kg + metronidazole 50 m/kg
Group 4 - pantoprazole 16 mg/kg + amoxicillin 120 mg/kg + clarithromycin 50 mg/kg
Group 5 - pantoprazole 16 mg/kg + clarithromycin 75 mg/kg + metronidazole 50 mg/kg
Histomorphological investigations indicated that treatment with clarithromycin and metronidazole alone (Group 2) induced an atrophic gastritis, which was not seen when these products were given concomitantly with pantoprazole. In Group 5, however, the total mucosal appearance was diagnosed as quite normal, and the height of the mucosa was not decreased. In the recovery dogs, the mucosae were also judged to be normal.
In all groups dosed with clarithromycin (Groups 2, 4, 5), inflammation and hyperplasia of the gallbladder, together with degeneration of the renal papilla were noted. These changes were absent from the Group 5 recovery dogs (only tubular swelling, increased tubular pigment noted), indicating reversibility. A slight centrilobular hypertrophy was observed in the liver of most animals.
In dogs which had positive 13C-urea breath tests prior to treatment, the Helicobacter-like organism responsible was eliminated in Groups 2 through 5, and remained eradicated in the Group 5 recovery animals.
Based on the results of this study, it was concluded that no additional toxic effects were observed during concomitant administration of different antibiotics with pantoprazole.
Three carcinogenicity studies had been conducted with pantoprazole:
- A 24 month oral study was conducted at doses of 0.5, 5, 50 and 200 mg/kg/day in SD rat.
- A 24 month oral study was conducted at doses of 5, 15 and 50 mg/kg/day in Fischer-344 rat.
- A 24 month oral study was conducted at doses of 5, 25 and 150 mg/kg/day in B6C3F1 mouse.
Pantoprazole, dissolved in distilled water, was administered once a day by oral gavage to groups of 50 male and 50 female B6C3F1 mice at doses of 5, 25, or 150 mg/kg. An identical control group was dosed with distilled water (pH 10), while a second identical control group received no treatment at all. In the first rat study, pantoprazole was administered once a day by oral gavage to groups of 70 male and 70 female SD rats at doses of 0.5, 5, 50, and 200 mg/kg. A control group of 70 males and 70 females received the vehicle. In the second rat study, pantoprazole was administered once a day by oral gavage to groups of 50 male and 50 female Fischer-344 rats at doses of 5, 15, and 50 mg/kg. A control group of 50 males and 50 females received the vehicle, while another group remained untreated.
In the first 2 year carcinogenicity study in rats, which corresponds to a lifetime treatment for rats, neuroendocrine neoplasms were found in the stomach at doses of 50 mg/kg/day and above in males and at 0.5 mg/kg/day and above in females. Tumor formation occurred late in the life of the animals (only after 17 months treatment), whereas no tumors were found in rats treated with an even higher dose for 1 year. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated, and it is considered to be due to high levels of serum gastrin observed in the rat during chronic treatment. In the second rat carcinogenicity study, neuroendocrine cell tumors in the stomach were found in all treated female groups and in the male 15 and 50 mg/kg groups. No metastases from any gastric neuroendocrine cell tumours were detected.
ECL-cell neoplasms were not observed in either the carcinogenicity study in the mouse (24 months) or in the chronic studies in the dog. In clinical studies, where pantoprazole was administered at doses up to 80 mg, ECL-cell density remained almost unchanged.
Microscopy of the rat (first carcinogenicity study) and mouse tissues gave evidence for an increase in liver tumors. In the rat experiment, the incidence of benign liver tumors in the 50 and 200 mg/kg groups and the incidence of hepatocellular carcinoma was increased in the males and females of the 200 mg/kg group. There was a slightly higher incidence of hepatocellular adenomas and carcinomas in the female mice of the 150 mg/kg group than in either of the
2 control groups. Other changes in the liver morphology were present as well. Centrilobular hepatocellular hypertrophy increased in incidence and severity with increasing dose, and hepatocellular necrosis was increased in the highest dose in the rat studies and in the mouse study. Hepatocellular tumors are common in mice, and the incidence found for the female
150 mg/kg group was within historical control ranges for this strain. The liver tumor incidences in rats treated with 50 mg/kg and in the male rats treated with 200 mg/kg were also within historical control incidences for the rat. These tumors occurred late in the life of the animals and were primarily benign. The nongenotoxic mechanism of rodent liver tumor formation after prolonged treatment with pantoprazole is associated with enzyme induction leading to hepatomegaly and centrilobular hypertrophy and is characterized by tumor induction in low incidences at high doses only. As pantoprazole acts in a similar fashion to phenobarbital, causing reversible centrilobular hepatocellular hypertrophy and enzyme induction in short-term studies, it is probable that the mechanism of action for induction of the liver tumors seen in long-term rodent studies is also the same. Hepatocellular tumors at high doses in rodents are not indicative of human carcinogenic risk.
A slight increase in neoplastic changes of the thyroid was observed in rats receiving pantoprazole at 200 mg/kg/day. The incidences of these tumours were within the historical control ranges for this rat strain. No thyroid neoplasms were observed in the 12-month study. The no-effect dose for both male and female rats is 50 mg/kg, which is 100 times the most commonly used human dose (i.e., 40 mg dose). The effect of pantoprazole on the thyroid is secondary to the effects on liver enzyme induction, which lead to enhanced metabolism of thyroid hormones in the liver. As a consequence, increased TSH is produced, which has a trophic effect on the thyroid gland. Clinical studies have demonstrated that neither liver enzyme induction nor changes in thyroid hormonal parameters occur in man after therapeutic doses of pantoprazole.
Tumors induced in rats and mice by pantoprazole were the result of nongenotoxic mechanisms which are not relevant to humans. Tumors were induced in rodents at dosages that provide higher exposure than with human therapeutic use. Based on kinetic data, the exposure to pantoprazole in rats receiving 200 mg/kg was 22.5 times higher than that found in humans receiving 40 mg oral doses. In mice receiving 150 mg/kg, exposure to pantoprazole was 2.5 times higher than that in humans.
Pantoprazole was studied in several mutagenicity studies: Pantoprazole was found negative in the Ames test, an in vivo chromosome aberration assay in rat bone marrow, a mouse lymphoma test, two gene mutation tests in Chinese hamster ovary cells in vitro, and two micronucleus tests in mice in vivo. Pantoprazole was found positive in three of four chromosome aberration assays in human lymphocytes in vitro. The in vitro tests were conducted both in the presence and absence of metabolic activation. The potential of pantoprazole to induce DNA repair synthesis was tested negative in an in vitro assay using rat hepatocytes. In addition, a rat liver DNA covalent binding assay showed no biologically relevant binding of pantoprazole to DNA.
In addition, two in vitro cell transformation assays using different cell types were performed to aid in the interpretation of the rodent carcinogenicity studies; in neither test did pantoprazole enhance the morphologic transformation of the cell types used.
A bacterial mutation assay conducted with the degradation product B8810-044, gave no indication of a mutagenic potential.
Reproduction and Teratology
Pantoprazole was not teratogenic to rats or rabbits at doses up to 450 and 40 mg/kg/day (gavage), 20 and 15 mg/kg/day (i.v. injection), respectively.
Treatment of male rats with pantoprazole up to 500 mg/kg p.o. for 127 days did not affect fertility. Treatment of pregnant rats induced dose-dependent fetotoxic effects: increased pre- and postnatal deaths (450 mg/kg/day), reduced fetal weight and delayed skeletal ossification (150 mg/kg/day), and reduced pup weight (15 mg/kg/day). These results may be explained by maternal toxicity of pantoprazole at high dose and/or placental transfer of pantoprazole.
Penetration of the placenta was investigated in the rat and was found to increase with advanced gestation. As a result, concentration of pantoprazole in the fetus is increased shortly before birth regardless of the route of administration.
In humans, there are no adequate or well-controlled studies with the use of pantoprazole during pregnancy.