Actions of Pantin in details
Pharmacology: Mechanism of Action: Pantin is a proton-pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the H+/K+-ATPase results in a duration of antisecretory effect that persists longer than 24 hrs of all doses tested.
Pharmacokinetics: Pantin does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following the administration of Pantin sodium for injection, the serum concentration of Pantin declines bioexponentially with a terminal elimination t½ of approximately 1 hr. In extensive metabolizers with normal liver function receiving a dose of Pantin 40 mg for injection by constant rate over 15 min, the peak concentration (Cmax) is 5.52 mcg/mL and the total area under the plasma concentration versus time curve (AUC) is 5.4 mcg hr/mL. The total clearance is 7.6-14 L/hr and apparent volume of distribution is 11-23.6 mL.
The serum protein-binding of Pantin is about 98% primarily to albumin. Pantin is extensively metabolized in the liver through the cytochrome P450 (CYP450) system.
After administration of a single IV dose of Pantin to healthy, normal stabilizer 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 Pantin.
How should I take Pantin?
Take Pantin exactly as prescribed by your doctor. Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Pantin tablets can be taken with or without food. Pantin oral granules should be taken 30 minutes before a meal.
Do not crush, chew, or break the tablet. Swallow it whole.
The oral granules should be mixed with applesauce or apple juice. Do not use any other type of liquid or soft food. Sprinkle the granules directly onto 1 teaspoon of applesauce or apple juice. Stir for 5 seconds and swallow this mixture right away without chewing. Do not save the mixture for later use.
To give Pantin granules through a nasogastric (NG) feeding tube:
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Attach a 60-milliliter syringe to the NG tube and remove the plunger. Hold the syringe high enough to prevent any bends in the tube.
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Empty the Pantin granules into the syringe barrel and mix in 2 teaspoons of apple juice.
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Add 2 more teaspoons of apple juice to the syringe to rinse the granules through. Tap or shake the syringe as the juice empties into the tube.
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Rinse with 2 teaspoons of apple juice at least twice more to make sure there are no granules remaining in the syringe or NG tube.
Take Pantin for the full prescribed length of time. Your symptoms may improve before the condition is fully treated.
If you use Pantin for longer than 3 years, you could develop a vitamin B-12 deficiency. Talk to your doctor about how to manage this condition if you develop it.
Call your doctor if your symptoms do not improve or if they get worse while you are taking this medicine.
If you use Pantin for longer than 3 years, you could develop a vitamin B-12 deficiency. Talk to your doctor about how to manage this condition if you develop it.
This medicine can cause you to have a false positive drug screening test. If you provide a urine sample for drug screening, tell the laboratory staff that you are taking Pantin.
Store Pantin at room temperature away from moisture and heat.
Pantin administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
Pantin tablets can be taken with or without food. Pantin oral granules should be taken 30 minutes before a meal.
Do not crush, chew, or break the tablet. Swallow it whole. The enteric-coated pill has a special coating to protect your stomach. Breaking the pill will damage this coating.
The oral granules should be mixed only with applesauce or apple juice to make swallowing easy. Do not use any other type of liquid or soft food. Sprinkle the granules directly onto a teaspoon of applesauce and swallow this mixture right away without chewing. Or pour the granules into a cup with 1 teaspoon of apple juice, stir for 5 seconds and swallow right away. To make sure you get the entire dose, add a little more apple juice to the same glass, swirl gently and drink right away. Do not save the granule mixture for later use.
To give Pantin granules through a nasogastric (NG) feeding tube:
- Attach a 60-milliliter syringe to the NG tube and remove the plunger. Hold the syringe high enough to prevent any bends in the tube.
- Sprinkle the Pantin granules into the syringe barrel and mix in 2 teaspoons of apple juice. Gently tap or shake the syringe as it empties into the tube.
- Add another 2 teaspoons of apple juice to the syringe to help rinse the granules through and to make sure the entire Pantin dose is given. Tap or shake the syringe as the juice empties into the tube.
- Repeat the rinse with 2 teaspoons of apple juice at least twice more, gently shaking the syringe as it empties into the tube. Make sure there are no granules remaining in the syringe or NG tube.
This medication can cause you to have a false positive drug-screening test. If you provide a urine sample for drug-screening, tell the laboratory staff that you are taking Pantin.
Take this medication for the full prescribed length of time. Your symptoms may improve before the condition is fully treated.
Call your doctor if your symptoms do not improve or if they get worse while you are taking this medicine.
Store at room temperature away from moisture and heat.
Pantin pharmacology
Mechanism of Action
Pantin 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 (20 mg to 120 mg).
Pharmacodynamics
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 to 80 mg) Pantin in healthy volunteers. Pantin given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg Pantin, 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%. Pantin 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 Pantin; there was no evidence of rebound hypersecretion.
In a series of dose-response studies, Pantin, at oral doses ranging 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 Pantin produced significantly greater increases in gastric pH 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 Pantin on median pH from one double-blind crossover study are shown in Table 4.
| Median pH on day 7 | ||||
|---|---|---|---|---|
| Time | Placebo | 20 mg | 40 mg | 80 mg |
| ||||
| 8 a.m. to 8 a.m. (24 hours) | 1.3 | 2.9* | 3.8*† | 3.9*† |
| 8 a.m. to 10 p.m. (Daytime) | 1.6 | 3.2* | 4.4*† | 4.8*† |
| 10 p.m. to 8 a.m. (Nighttime) | 1.2 | 2.1* | 3.0* | 2.6* |
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 Pantin 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 Pantin dose groups. Median serum gastrin levels remained within normal limits during maintenance therapy with Pantin Sodium Delayed-Release 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 treatment with Pantin 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 short-term treatment with Pantin, elevated gastrin levels return to normal by at least 3 months.
Enterochromaffin-Like (ECL) Cell Effects
In 39 patients treated with oral Pantin 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 Pantin 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 Pantin 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 Pantin at 5 mg/kg/day and a 9 month off-dose recovery.
Pharmacokinetics
Pantin Sodium Delayed-Release Tablets are prepared as enteric-coated tablets so that absorption of Pantin begins only after the tablet leaves the stomach. Peak serum concentration (Cmax) and area under the serum concentration time curve (AUC) increase in a manner proportional to oral doses from 10 mg to 80 mg. Pantin does not accumulate, and its pharmacokinetics are unaltered with multiple daily dosing. Following oral administration, the serum concentration of Pantin declines biexponentially, with a terminal elimination half-life of approximately one hour.
In extensive metabolizers with normal liver function receiving an oral dose of the enteric-coated 40 mg Pantin tablet, the peak concentration (Cmax) is 2.5 mcg/mL; the time to reach the peak concentration (tmax) is 2.5 h, and the mean total area under the plasma concentration versus time curve (AUC) is 4.8 mcg∙h/mL (range 1.4 to 13.3 mcg∙h/mL).
Absorption
After administration of a single or multiple oral 40 mg doses of Pantin Sodium Delayed-Release Tablets, the peak plasma concentration of Pantin was achieved in approximately 2.5 hours, and Cmax was 2.5 mcg/mL. Pantin undergoes little first-pass metabolism, resulting in an absolute bioavailability of approximately 77%. Pantin absorption is not affected by concomitant administration of antacids.
Administration of Pantin Sodium Delayed-Release Tablets with food may delay its absorption up to 2 hours or longer; however, the Cmax and the extent of Pantin absorption (AUC) are not altered. Thus, Pantin Sodium Delayed-Release Tablets may be taken without regard to timing of meals.
Distribution
The apparent volume of distribution of Pantin is approximately 11.0 to 23.6 L, distributing mainly in extracellular fluid. The serum protein binding of Pantin is about 98%, primarily to albumin.
Metabolism
Pantin is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantin metabolism is independent of the route of administration (oral or intravenous). 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 Pantin metabolites have significant pharmacologic activity.
Elimination
After a single oral dose of 14C-labeled Pantin to healthy, normal metabolizer volunteers, 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 Pantin.
Geriatric
Only slight to moderate increases in Pantin AUC (43%) and Cmax (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 Pantin were studied in children less than 16 years of age in four randomized, open-label clinical trials in pediatric patients with presumed/proven GERD. A pediatric granule formulation was studied in children through 5 years of age, and Pantin Delayed-Release Tablets were studied in children older than 5 years.
In a population PK analysis, total clearance increased with increasing bodyweight in a non-linear fashion. The total clearance also increased with increasing age only in children under 3 years of age.
Neonate through 5 years of age
Children and Adolescents 6 through 16 Years of Age
The pharmacokinetics of Pantin Sodium Delayed-Release Tablets were evaluated in children ages 6 through 16 years with a clinical diagnosis of GERD. The PK parameters following a single oral dose of 20 mg or 40 mg of Pantin tablets in children ages 6 through 16 years were highly variable (%CV ranges 40 to 80%). The geometric mean AUC estimated from population PK analysis after a 40 mg Pantin tablet in pediatric patients was about 39% and 10% higher respectively in 6 to 11 and 12 to 16 year-old children, compared to that of adults (Table 5).
| 6 to 11 years (n=12) | 12 to 16 years (n=11) | |
|---|---|---|
| ||
| Cmax (mcg/mL)* | 1.8 | 1.8 |
| Tmax (h)† | 2.0 | 2.0 |
| AUC (mcg∙h/mL)* | 6.9 | 5.5 |
| CL/F (L/h)† | 6.6 | 6.8 |
Gender
There is a modest increase in Pantin AUC and Cmax in women compared to men. However, weight-normalized clearance values are similar in women and men. No dosage adjustment is recommended based on gender. In pediatric patients ages 1 through 16 years there were no clinically relevant effects of gender on clearance of Pantin, as shown by population pharmacokinetic analysis.
Renal Impairment
In patients with severe renal impairment, pharmacokinetic parameters for Pantin were similar to those of healthy subjects. No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis.
Hepatic Impairment
In patients with mild to severe hepatic impairment (Child-Pugh A to C cirrhosis), maximum Pantin concentrations increased only slightly (1.5-fold) relative to healthy subjects. Although serum half-life values increased to 7 to 9 hours and AUC values increased by 5- to 7-fold in hepatic-impaired patients, these increases were no greater than those observed in CYP2C19 poor 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. 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
Pantin 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] and clopidogrel), 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 Pantin were not significantly altered.
Clopidogrel is metabolized to its active metabolite in part by CYP2C19. In a crossover clinical study, 66 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with Pantin (80 mg at the same time as clopidogrel) for 5 days. On Day 5, the mean AUC of the active metabolite of clopidogrel was reduced by approximately 14% (geometric mean ratio was 86%, with 90% CI of 79 to 93%) when Pantin was coadministered with clopidogrel as compared to clopidogrel administered alone. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 µM ADP) was correlated with the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear.
Mycophenolate Mofetil (MMF): Administration of Pantin 40 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of Pantin to 12 healthy subjects in a cross-over study resulted in a 57% reduction in the Cmax and 27% reduction in the AUC of MPA. Transplant patients receiving approximately 2000 mg per day of MMF (n=12) were compared to transplant patients receiving approximately the same dose of MMF and Pantin 40 mg per day (n=21). There was a 78% reduction in the Cmax and a 45% reduction in the AUC of MPA in patients receiving both Pantin and MMF.
In vivo studies also suggest that Pantin does not significantly affect the kinetics of the following drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]). Dosage adjustment of these drugs is not necessary when they are coadministered with Pantin. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with Pantin.
Based on studies evaluating possible interactions of Pantin with other drugs, no dosage adjustment is needed with concomitant use of the following: theophylline, cisapride, antipyrine, caffeine, carbamazepine, diazepam (and its active metabolite, desmethyldiazepam), diclofenac, naproxen, piroxicam, digoxin, ethanol, glyburide, an oral contraceptive (levonorgestrel/ethinyl estradiol), metoprolol, nifedipine, phenytoin, warfarin, midazolam, clarithromycin, metronidazole, or amoxicillin.
There was also no interaction with concomitantly administered antacids.
There have been postmarketing reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including Pantin, and warfarin concomitantly.
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 Pantin has not been studied in poor metabolizers or individuals who are hepatically impaired.
Other Effects
In a clinical pharmacology study, Pantin 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), 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 Pantin 40 mg or 20 mg, there were no changes from baseline in overall levels of T3, T4, and TSH.
Pharmacogenomics
CYP2C19 displays a known genetic polymorphism due to its deficiency in some subpopulations (e.g., approximately 3% of Caucasians and African-Americans and 17% to 23% of Asians are poor metabolizers). Although these subpopulations of Pantin poor metabolizers have elimination half-life values of 3.5 to 10.0 hours in adults, they still have minimal accumulation (≤ 23%) with once-daily dosing. For adult patients who are CYP2C19 poor metabolizers, no dosage adjustment is needed.
Similar to adults, pediatric patients who have the poor metabolizer genotype of CYP2C19 (CYP2C19 *2/*2) exhibited greater than a 6-fold increase in AUC compared to pediatric extensive (CYP2C19 *1/*1) and intermediate (CYP2C19 *1/*x) metabolizers. Poor metabolizers exhibited approximately 10-fold lower apparent oral clearance compared to extensive metabolizers.
For known pediatric poor metabolizers, a dose reduction should be considered.
References
- EPA DSStox. "Pantoprazole: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
