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Esomeprazole (Nexium™):
A New Proton Pump Inhibitor

Volume IV, Number 4 | July/August 2001
Mandy Leonard, Pharm.D., BCPS

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Introduction

In 1989, the FDA approved the first proton pump inhibitor (PPI) in the United States, omeprazole (Prilosec™). Lansoprazole (Prevacid®) was the second FDA-approved PPI in 1995, followed by rabeprazole (Aciphex™) in 1999 and pantoprazole (Protonix®) in 2000. Esomeprazole (Nexium™) received FDA-approval in 2001 and is the S-isomer of omeprazole.

Indications

Esomeprazole is FDA-approved for the treatment of symptomatic gastroesophageal reflux disease (GERD), short-term treatment of erosive esophagitis, and maintenance of erosive esophagitis healing. It is also approved for use with antibiotics for the treatment of Helicobacter pylori-associated duodenal ulcers. See Table 1

Table 1. FDA-approved indications of the Proton Pump Inhibitors
Indication Esomeprazole
(Nexium™)
Lansoprazole
(Prevacid®)
Omeprazole
(Prilosec™)
Pantoprazole
(Protonix®)
Rabeprazole
(Aciphex™)
Healing of erosive esophagitis X X X X X
Maintenance of healed erosive esophagitis X X X X X
Symptomatic gastroesophageal
reflux disease
X X X X   
Eradication of Heliobacter pylori infection X X X    
Prevention of NSAID-induced gastric ulcers   X        
Treatment of NSAID-induced gastric ulcers    X          
Healing of gastric ulcer    X X      
Healing of duodenal ulcer    X X    X
Maintenance of duodenal ulcer    X         
Treatment of pathological hypersecretory conditions
(eg, Zollinger-Ellison Syndrome)
   X X    X


Clinical Pharmacology

Esomeprazole works by binding irreversibly to the H+/K+ ATPase in the proton pump. Because the proton pump is the final pathway for secretion of hydrochloric acid by the parietal cells in the stomach, its inhibition dramatically decreases the secretion of hydrochloric acid into the stomach and alters gastric pH. This is the same mechanism of action as omeprazole and the other PPIs.

Pharmacokinetics

(See Table 2) Esomeprazole is the S-isomer of omeprazole. It must be administered using an enteric-coated formulation, which delays release of the drug to the alkaline portion of the gastrointestinal tract. Peak plasma concentrations occur 1.56 to 2.3 hours after oral administration on an empty stomach. Esomeprazole is eliminated from the body by hepatic metabolism to inactive metabolites. Hepatic metabolism is performed by the cytochrome P-450 system, specifically the isoenzymes CYP2C19 (73%) and CYP3A4 (27%). Less than 1% of esomeprazole is excreted unchanged in the urine, with 80% excreted renally and the remainder excreted in the feces. The elimination half-life of esomeprazole following single-dose oral administration is 0.85 hours. The half-life increases to 1.2 to 1.5 hours after 5 days of oral administration. The volume of distribution of esomeprazole is 16 to 18 L. Alterations in renal function have no effect on esomeprazole's pharmacokinetics, while patients with liver cirrhosis will have a small delay in the time-to-peak plasma concentration (2 vs 1.56 hours). The geometric mean AUC is increased by 76%, and the half-life is increased by 29%. Mild-to-moderate hepatic dysfunction has no effect on the pharmacokinetics of esomeprazole. Severe hepatic dysfunction (Child-Pugh Class C) can increase the AUC and half-life of esomeprazole.

Table 2. Comparison of the Pharmacokinetic Parameters of Various PPIs


Parameter Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole
Bioavailablitiy 90% 80% 30-40% 77% 52%
Acid liable Yes Yes Yes Yes Yes
Enteric-coated formulation Yes Yes Yes Yes Yes
Time to peak 1.5 hours 1.7 hours 0.5-3.5 hours 2.5 hours 2-5 hours
Half-life 1.2-1.5 hours < 2 hours 0.5-1 hour -1.9 hours 1-2 hours
Excreted unchanged in the urine < 1% < 1% 0 % 0 % 0 %
Cytochrome P450 pathway* CYP2C19,
CYP3A4
CYP3A, CYP2C19 CYP2C9,
CYP2C8,
CYP2C18,
CYP2C19, CYPA3/4,
CYP3A1A2
CYP2C19, CYP3A4 CYP3A, CYP2C19
Protein binding 97% 97%
95%
98%
96.3%

* = predominate pathway is highlighted in bold

Adverse Reactions

The adverse events associated with esomeprazole therapy are generally similar to those seen with the placebo and omeprazole therapy. This is similar to the previously available PPIs. The most common adverse events reported in the clinical trials were diarrhea, abdominal pain, flatulence, gastritis, nausea, and headache.

Drug-Drug Interactions

Drug interactions reported with omeprazole have included prolonged elimination of diazepam, warfarin, and phenytoin. Isolated reports of changes in elimination have been reported with cyclosporine, disulfiram, and other benzodiazepines. See Table 3. No drug-drug interactions were found between esomeprazole and phenytoin, R-warfarin, quinidine, amoxicillin, oral contraceptives, and clarithromycin. Esomeprazole may interfere with the elimination of other drugs metabolized by CYP2C19. Coadministration of esomeprazole and diazepam results in a 45% reduction in diazepam clearance and increased plasma diazepam levels. Changes in gastric pH can affect the bioavailability of some medications. Examples of medications where the bioavailability of the medication may be decreased with profound and long-lasting inhibition of gastric acid secretion are ketoconazole and iron salts.

Table 3. Drug Interactions Reported in the Product Labeling of Various PPIs
Drug Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole
Drugs dependent on gastric pH for absorption*
X
X
X
X
X
Benzodiazepines      
X
     
Cyclosporine
  
  
X
  
  
Diazepam
X
  
X
  
  
Digoxin
  
  
X
  
X
Disulfiram
  
  
X
  
  
Phenytoin
  
  
X
  
  
Theophylline
  
X
  
  
  
Warfarin
  
  
X
  
  

* = decreased absorption of drugs requiring acidic pH for absorption (eg, ketoconazole, ampicillin, iron)

Dosage and Administration

(See table 4). The recommended dose of esomeprazole is 20 mg or 40 mg once daily for 4 to 8 weeks for the treatment of erosive esophagitis, 20 mg once daily for maintenance of healed erosive esophagitis (studies lasted up to 6 months), 20 mg once daily for symptomatic GERD for 4 weeks, and as part of a 10-day triple drug regimen for eradication of H. pylori infections (the esomeprazole will be given as a single dose). The regimen recommended for the eradication of H. pylori infection is esomeprazole 40 mg once daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily for 10 days. The capsule should be swallowed whole 1 hour before eating. If the patient has difficulty swallowing the capsule, it can be opened and mixed with applesauce and taken immediately. The applesauce should not be hot and should be soft enough to be swallowed without chewing. The pellet should not be chewed or crushed. It may also be mixed with tap water, orange juice, apple juice, or yogurt.

Table 4. Comparison of FDA-Approved Dosing Regimens for Various PPIs
Indication Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole
Symptomatic GERD 20 mg QD
x 4 weeks
15 mg QD
up to 8 weeks
20 mg QD
x 4 weeks*
     
Healing erosive esophagitis 20-40 mg QD
x 4-8 weeks
30 mg QD
up to 8 weeks
20 mg QD
x 4-8 weeks
40 mg QD
up to 8 weeks
20 mg QD
x 4-8 weeks
Maintenance of erosive esophagitis 20 mg QD 15 mg QD 20 mg QD    20 mg QD
Hypersecretory conditions
(eg, ZES)
   60 mg QD 60 mg QD; 80-360 mg/day    60 mg QD; 100 mg QD-60 mg BID
Duodenal ulcers    15 mg QD
x 4 weeks
20 mg QD x 4 weeks*    20 mg QD
up to 4 weeks
Duodenal ulcers-maintenance    15 mg QD         
Gastric ulcers   30 mg QD
up to 8 weeks
40 mg QD
x 4-8 weeks
    
H. pylori eradication 40 mg QD
x 10 days
plus antibiotics
30 mg BID
plus antibiotics
x 10-14 days; 30 mg TID
plus amoxicillin x 14 days
20 mg BID plus antibiotics x 10 days, followed by 20 mg QD X 18 days; 40 mg QD plus clarithromycin x 14 days, followed by 20 mg QD x 14 days      
Treatment of NSAID-induced gastric ulcers    30 mg QD x 8 weeks         
Prevention of NSAID-induced gastric ulcers    15 mg QD up to 12 weeks         

QD = once daily; BID = twice daily; TID = three times daily
* = If symptoms do not resolve completely after 4 weeks, an additional 4 weeks of treatment may be considered.

Table 5. Cost Comparison
PPI Average Wholesale Price (AWP) (30-day)
Esomeprazole 20 mg $119.90
Esomeprazole 40 mg $119.90
Lansoprazole 15 mg $117.65
Lansoprazole 30 mg $399.66
Omeprazole 10 mg $111.25
Omeprazole 20 mg $124.17
Omeprazole 40 mg $178.20
Pantoprazole 40 mg $93.60
Rabeprazole 20 mg >$113.99

 

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Center for Continuing Education | 1950 Richmond Road, TR204, Lyndhurst, OH 44124