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By My-Trang Le, PharmD, RPh
Clinical Pharmacy Coordinator Critical Care
Saint Vincent Hospital
Steven Cano, MS, RPh
Director of Pharmacy
Saint Vincent Hospital
Since the U.S. market approval of omeprazole 12 years ago, a growing number of drugs have been added to the benzimidazole proton pump inhibitor (PPI) class. Currently, five agents have U.S. Food and Drug Administration (FDA) approval for oral use (esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole). Of that group, only pantoprazole (Protonix IV) also is FDA-approved for intravenous (IV) use.
Oral (PO) PPIs have become very widely used over the past decade and now represent a multi-billion-dollar market in the United States alone.
The market introduction of IV pantoprazole offers clinicians the potential for additional therapeutic flexibility. Injectable omeprazole (and to a lesser extent lansoprazole) has been studied extensively in world-wide clinical trials with success. These agents have not been introduced to the U.S. market to date, in spite of their clinical promise, likely due to pharmaceutical (e.g., stability and formulation) challenges.
The introduction of an injectable form of a PPI has created considerable interest among hospital pharmacists and other clinicians. The challenge for pharmacy and therapeutics (P&T) committees everywhere will be to carefully manage the use of IV pantoprazole through proper identification of acceptable indications and durations of treatment (both in the absence of optimal clinical information). The issue of the optimal route of PPI administration (i.e., IV vs. PO vs. nasogastric [NG]) also will be the subject of considerable P&T committee debate due to both efficacy and cost implications.
Pantoprazole demonstrates linear kinetics between dosing and peak serum concentration (CMAX) or serum concentration under the curve (CAUC) in the dosage range of 10-80 mg. Following the infusion of a 40 mg dose, the CMAX is 4.6-5.5 mcg/mL and the CAUC is 5.4 mcg-h/mL. Time to peak concentration is achieved at the end of the infusion.
Distribution. The apparent volume of distribution of pantoprazole is approximately 11-23.6 L with limited tissue distribution. Plasma protein binding of pantoprzole is ~ 98%, primarily to albumin.
Metabolism. Pantoprazole is extensively metabolized by the liver via cytochrome P-450-mediated oxidation followed by sulfate conjugation. The main metabolic pathway is CYP 2C19. In patients with mild-to-moderate hepatic impairment, metabolism is impaired; however, dosage adjustment may not be required because peak plasma concentration is elevated marginally. Pantoprazole does not appear to cause any induction or inhibition of the cytochrome P-450 enzyme system.
Elimination. Seventy-one percent of the dose is excreted in the urine as metabolites and 18% is excreted in the feces through biliary excretion. Hemodialysis and renal impairment do not have clinically significant effects on elimination. Pantoprazole has an average half-life of 1.9 hours (0.8-5.1 hours). The half-life is prolonged to 7-9 hours in patients with hepatic cirrhosis or among slow metabolizers. Caution should be exercised when administered IV pantoprazole in these populations.
Mechanism of action. As with the other drugs in the PPI class, pantoprazole reduces gastric acid secretion through inhibition of the proton pump on the gastric parietal cell. In the strongly acidic environment (i.e., pH < 3), pantoprazole (a weak base, pKa = 3.9) is converted rapidly to an active form, a cation cyclic sulfonamide, which binds covalently to cysteine residues on the surface of parietal H+/K+ ATPase, thereby causing irreversible inhibition of the proton pump function. As H+/K+ ATPase represents the final step in the secretory process, inhibition of this enzyme suppresses gastric acid secretion regardless of the primary stimulus.
Effects on gastric secretions. Suppression of the 24-hour accumulative pentagastrin-stimulated acid output (PSAO) of single-dose pantoprazole is dose-related over the range of 20-80 mg. Complete suppression was achieved with 80 mg dosing; no further inhibition was observed with higher doses (120 mg). As noted with other antisecretory agents, serum gastrin level was elevated three- to four-fold compared with placebo following the administration of multiple pantoprazole doses. Gastric level came back to normal range 24 hours following the administration of the last dose.
Other effects. Unlike cimetidine or omeprazole, pantoprzole does not interfere with cortisol synthesis. It also is reported to not significantly affect basal plasma thyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, or somatotrophic hormone levels.
IV pantoprazole has been very well-tolerated in clinical trials of gastroesophageal reflux disease (GERD) patients and healthy volunteers. The most frequent adverse effects potentially related to IV pantoprazole therapy include abdominal pain (12%), chest pain (6%), rash (6%), and pruritis (4%). Injection site reactions also have been reported. The adverse effects of pantoprazole were equally tolerated relative to cimetidine or ranitidine in the "German pantoprazole phase IV program."
Of all the proton pump inhibitors available, pantoprazole has the lowest affinity for the hepatic cytochrome P-450 enzyme system in animal studies. In contrast to omeprazole and cimetidine, pantoprazole does not show remarkable interactions with substrates for the CYP-450 1A, 2C, and 3A subfamilies of the isoenzyme.
In healthy volunteers, pantoprazole has shown a lack of clinically significant interactions with diazepam, digoxin, theophylline, carbamazepine, diclofenac, warfarin, nifedipine, caffein, metoprolol, or ethanol.
A survey of the clinical literature identifies a variety of potential therapeutic uses for IV pantoprazole. The positioning of this agent within the institution will depend upon its efficacy and cost relative to other existing therapeutic options (e.g., histamine-2 receptor antagonists [H2A]). A summary of the potential therapeutic uses for IV pantoprazole is found in Table 1, below.
Pantoprazole is available in an injectable dosage form as a freeze-dried powder in a glass vial. When treating GERD, each vial (40 mg) should be reconstituted with 10 mL of 0.9% sodium chloride for injection and further diluted with 100 mL of solution (0.9% sodium chloride, dextrose 5% in water, or lactated Ringer’s) for a final concentration of 0.4 mg/mL. The dose should be administered IV once daily for 7-10 days. The drug should be infused over 15 minutes (at a rate not to exceed 3 mg/min) with a filter to remove the precipitate that may form when the reconstituted drug is diluted.
No dosing adjustments are required in patients with renal insufficiency (including those undergoing hemodialysis), mild or moderate hepatic insufficiency, or the elderly. The pharmacokinetics of IV pantoprazole have not been well characterized in patients with severe hepatic impairment.
There is little consensus to support any particular dosing strategy with regard to IV pantoprazole in non-FDA approved clinical situations. It is likely that clinicians will develop a feel for optimal dosing through clinical experience before FDA-approved labeling is available. The P&T committee can play an important role in the accumulation of data related to non-FDA approved indications.
Pantoprazole is the only PPI commercially available in an IV dosage form; as a result, it should be available on the hospital formulary for use in selected patients. The specific patient population(s) targeted should be determined based on an ongoing evaluation of clinical literature and through discussions among pharmacists, gastroenterologists, and intensivists.
To date, there is considerably more published clinical information available for IV omeprazole (on the market in Europe and Asia) than for IV pantoprazole. P&T committees will likely need to extrapolate IV omeprazole data in some cases as policy decisions are made. It may be particularly difficult at the current time to come to a consensus on dosing guidelines for the various clinical situations.
For reasons of efficacy and cost, IV pantoprazole should be used only when the PO and/or NG route of administration is not feasible or an H2A IV is not an equivalent therapeutic option.
Given the dynamic nature of the U.S. PPI market, very interesting contract scenarios are being promoted for the PO agents. The ultimate cost of IV pantoprazole to the institution may be greatly influenced by the decisions made relative to the PO PPI formulary.
Table 2, below, summarizes the various actions P&T committees should consider when evaluating IV pantoprazole for formulary purposes.
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