Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: Sandoz SA (Pty) Ltd, 72 Steel Road, Spartan, Kempton Park, 1619
Pharmacological classification: A 11.4.3 Medicines acting on the gastrointestinal tract
ATC Code: A02BC02 – Proton pump inhibitors
Pantoprazole is a substituted benzimidazole, which inhibits the secretion of hydrochloric acid in the stomach by specific blockade of the proton pumps of the parietal cells. Pantoprazole is converted to its active form, a cyclic sulphenamide, in the acidic environment in the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach.
The inhibition is dose-dependent and affects both basal and stimulated acid secretion. In most patients, freedom from symptoms is achieved within 2 weeks. As with other proton pump inhibitors and H2 receptor inhibitors, treatment with pantoprazole reduces acidity in the stomach and thereby increases gastrin in proportion to the reduction in acidity. The increase in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the receptor level, it can inhibit hydrochloric acid secretion independently of stimulation by other substances (acetylcholine, histamine, gastrin). The effect is the same whether the active substance is given orally or intravenously.
Pantoprazole exerts its full effect in a strongly acidic environment (pH <3) and remains mostly inactive at higher pH values, which explains its selectivity for the acid secreting parietal cells of the stomach. Therefore, the complete pharmacological and therapeutic effect for pantoprazole can only be achieved in the acid- secreting parietal cells. By means of a feedback mechanism, this effect is diminished at the same rate as acid secretion is inhibited
Following oral administration, pantoprazole inhibits the pentagastrin stimulated gastric acid secretion. The mean acid inhibition was 85%, two-and-a-half to three-and-a-half hours after dosing with 40 mg/day for 7 days. Pantoprazole maintains the physiological pH-rhythm. The values, however, are shifted to higher levels. During the night, periods of pH-values approximating placebo have been found to occur.
Although pantoprazole has a 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.
The fasting gastrin values increase under pantoprazole. On short-term use, in most cases they do not exceed the upper limit of normal. During long-term treatment, gastrin levels double in most cases. An excessive increase, however, occurs only in isolated cases. As a result, a mild to moderate increase in the number of specific endocrine (ECL) cells in the stomach is observed in a minority of cases during long-term treatment (simple to adenomatoid hyperplasia). However, according to the studies conducted so far, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids as were found in animal experiments (see section 5.3) have not been observed in humans.
During treatment with antisecretory medicinal products, serum gastrin increases in response to the decreased acid secretion. Also CgA increases due to decreased gastric acidity. The increased CgA level may interfere with investigations for neuroendocrine tumours. Available published evidence suggests that proton pump inhibitors should be discontinued between 5 days and 2 weeks prior to CgA measurements. This is to allow CgA levels that might be spuriously elevated following PPI treatment to return to reference range.
An influence of a long-term treatment with pantoprazole exceeding one year cannot be completely ruled out on endocrine parameters of the thyroid according to results in animal studies.
Pantoprazole is rapidly absorbed and the maximum plasma concentration is achieved even after one single 20 mg and 40 mg oral dose. On average, at about 2,0 h – 2,5 h p.a. (20 mg pantoprazole) and 2,5 h p.a. (40 mg pantoprazole) the maximum serum concentrations of about 1 to 1,5 µg/ml (20 mg pantoprazole) and 2 to 3 µg/ml (40 mg pantoprazole) are achieved, and these values remain constant after multiple administration.
Pharmacokinetics do not vary after single or repeated administration. In the dose range of 10 to 80 mg the plasma kinetics of pantoprazole are linear after both oral and intravenous administration.
The absolute bioavailability from the tablet was found to be about 77%. Concomitant intake of food had no influence on AUC, maximum serum concentration and thus bioavailability. Only the variability of the lag-time will be increased by concomitant food intake.
Pantoprazole’s serum protein binding is about 98%. Volume of distribution is about 0,15 l/kg.
Pantoprazole is almost exclusively metabolised in the liver. The main metabolic pathway is demethylation by CYP2C19 with subsequent sulphate conjugation, other metabolic pathways include oxidation by CYP3A4.
Terminal half-life is about 1 hour and clearance is about 0,1 l/h/kg. There were a few cases of subjects with delayed elimination. Because of the specific binding of pantoprazole to the proton pumps of the parietal cell the elimination half-life does not correlate with the much longer duration of action (inhibition of acid secretion).
Renal elimination represents the major route of excretion (approximately 80%) for the metabolites of pantoprazole, the rest is excreted with the faeces.
The main metabolite in both the serum and urine is desmethylpantoprazole, which is conjugated with sulphate. The half-life of the main metabolite (about 1½ hours), is not much longer than that of pantoprazole.
No dose reduction is recommended when pantoprazole is administered to patients with impaired renal function (including dialysis patients). As with healthy subjects, pantoprazole’s half-life is short. Only very small amounts of pantoprazole are dialysed. Although the main metabolite has a moderately delayed half-life (2-3 h), excretion is still rapid and thus accumulation does not occur.
Although for patients with liver cirrhosis (classes A and B according to Child), the half-life values increased to between 3 and 6 h (pantoprazole 20 mg) and 7 to 9 hours (pantoprazole 40 mg), and the AUC values increased by a factor of 3-5 (pantoprazole 20 mg) and 5 to 7 (pantoprazole 40 mg), the maximum serum concentration only increased slightly by a factor of 1,3 (pantoprazole 20 mg) and 1,5 (pantoprazole 40 mg) compared with healthy subjects.
A slight increase in AUC and Cmax in elderly volunteers compared with younger counterparts is also not clinically relevant.
Following administration of single oral doses of 20 mg or 40 mg pantoprazole to children aged 5-16 years AUC and Cmax were in the range of corresponding values in adults.
Following administration of single i.v. doses of 0,8 or 1,6 mg/kg pantoprazole to children aged 2-16 years there was no significant association between pantoprazole clearance and age or weight. AUC and volume of distribution were in accordance with data from adults.
Non-clinical data reveal no special hazard to humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
In the two-year carcinogenicity studies in rats, neuroendocrine neoplasms were found. In addition, squamous cell papillomas were found in the forestomach of rats in one study. The mechanism leading to the formation of gastric carcinoids by substituted benzimidazoles has been carefully investigated and allows the conclusion that it is a secondary reaction to the massively elevated serum gastrin levels occurring in the rat during chronic high-dose treatment. In the two-year rodent studies, an increased number of liver tumours was observed in rats (in one rat study only) and in female mice and was interpreted as being due to pantoprazole’s high metabolic rate in the liver.
A slight increase of neoplastic changes of the thyroid was observed in the group of rats receiving the highest dose (200 mg/kg) in one 2-year study. The occurrence of these neoplasms is associated with the pantoprazole-induced changes in the breakdown of thyroxine in the rat liver. As the therapeutic dose in man is low, no harmful effects on the thyroid glands are expected.
In animal studies (rats) 5 mg/kg was the observed NOAEL (No Observed Adverse Effect Level) for embryotoxicity.
Investigations revealed no evidence of impaired fertility or teratogenic effects.
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 foetus is increased shortly before birth.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
