Advances in Proton Pump Inhibitor Therapy: THE ADVENT OF IMMEDIATE-RELEASE OMEPRAZOLE

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15 Apr 2010

Approximately one year ago, the U.S. Food and Drug Administration (FDA) approved a unique IR formulation (Zegerid) to treat a variety of acid-related disorders and to reduce the risk of upper gastrointestinal bleeding in critically ill patients (Table 1). This compound was developed by combining a highly effective PPI (omeprazole) with an antacid buffer (sodium bicarbonate), which neutralizes gastric acid and protects the PPI from gastric acid degradation.

Studies have found that the degradation half-life of non-enteric-coated ome-prazole is approximately seven hours at a pH of 6, compared to less than three minutes at a pH of 1.2. In an in vitro model, the sodium bicarbonate buffer in IR-OME rapidly increases the pH to greater than 6 within one minute and sustains this pH environment for approximately 30 minutes. This pharmacological synergy protects omeprazole from gastric acid degradation, allows it to be rapidly absorbed, and eliminates the need for an enteric coating.

Table 1 Uses and Dosages of Immediate-Release Omeprazole (IR-OME) Powder for Suspension

Indication Dose
1. Short-term treatment of active 1. 20 mg once daily for four weeks;
duodenal ulcer some patients may require an
additional four weeks of therapy.
2. Gastric ulcer 2. 40 mg once daily for four to eight
weeks.
3. GERD; symptomatic, no 3. 20 mg once daily for up to four
esophageal lesions weeks
4. GERD; symptomatic with confirmed 4. 20 mg once daily for four to eight
erosive esophagitis weeks
5. Maintenance of healing of 5. 20 mg once daily; controlled studies
erosive esophagitis do not extend beyond 12 months.
6. Reduction in risk of upper 6. 40 mg initially, followed by 40 mg
gastrointestinal bleeding in critically after six to eight hours as a loading
ill patients dose on the first day, then 40 mg
once daily for up to 14 days; the use
of IR-OME in critically ill patients
for longer than 14 days has not been
evaluated.
GERD = gastroesophageal reflux disease.

PHARMACOKINETICS

The pharmacokinetic profile of IR-OME differs significantly from that of a delayed-release PPI plus an antacid. Specifically, the Cmax of the IR formulation is achieved in 10 to 90 minutes (mean, 30 minutes) after single or multiple oral doses are taken on an empty stomach. In contrast, several investigators, studying the pharmacokinetics of delayed-release omeprazole or rabepra-zole, coadministered with antacids, found no significant change in the Cmax, the mean time to peak plasma concentration (Tmax), or the area under the curve (AUC). One study of delayed-release lansoprazole, given with an antacid, revealed a slight decrease in the AUC and a significant decrease in the Cmax with no change in the Tmax.

In an open-label, randomized, two-period crossover comparator trial with a 10- to 14-day washout period between treatments, IR-OME in strengths of 40 and 20 mg was compared with delayed-release 40- and 20-mg omeprazole capsules. During each treatment period, healthy subjects received seven consecutive single daily doses of each dosage strength one hour before they ate a standardized high-fat breakfast.

Table 2 Mean Pharmacokinetic Parameters after Administration of Omeprazole on Days One and Seven

A, Immediate-Release Omeprazole
Day One Day Seven
Parameter

40 mg

20 mg

40 mg

20 mg

AUC^ (ng • hour/ml)       2,228

825

4,640

1,446

Cmax(ng/ml)

1,412

672

1,954

902

T    (minutes)max V               I

26.6

29.8

34.7

28.3

Half-life (hours)

1.00

0.86

1.38

1.08

B, Delayed-Release Omeprazole canadian
Day One Day Seven
Parameter

40 mg

20 mg

40 mg

20 mg

AUC^ (ng • hour/ml)       2,658

903

4,591

1,351

Cmax(ng/ml)

1,040

461

1,677

573

Tmax(hours)

2.34

1.74

1.77

1.39

Half-life (hours) 1.21

1.21

1.42

1.30

AUC = area under the curve; C    = maximum concentration; T’max                                                    ‘ max = time to maximumax
concentration.

As illustrated in Figure 1, the Tmax observed with each dosage strength of the IR formulation occurred much sooner (P < .001) (at approximately 30 minutes with each dose) than that of the respective dose of the enteric-coated formulation (at 1.8 and 1.4 hours, respectively) with delayed-release omeprazole 40 mg and 20 mg (Table 2).

The AUC of IR-OME 40 mg is about three-fold higher than that of the 20-mg dose, and repeated exposure to the IR form results in increased bioavailability. The observed increase in the AUC is almost doubled from a single dose, compared with the steady state (Table 2). Because taking IR-OME one hour after a meal decreases the AUC by approximately 26% at steady state, optimal phar-macokinetic parameters are achieved when patients take this drug on an empty stomach. However, the AUC associated with a postprandial 40-mg dose of IR-OME is still substantial (3,862 ng • hour/ml) in the range associated with a 70% reduction in baseline gastric acidity.
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Figure 1 A, B, Mean plasma concentrations of immediate-release omeprazole

Figure 1 A, 6, Mean plasma concentrations of immediate-release omeprazole (IR-OME) suspension and delayed-release omepra-zole capsules on days one and seven. Both compounds were administered one hour before mealtime. The mean time to peak plasma concentration (Tmax) with these doses occurred significantly sooner (at approximately 30 minutes) (Table 2A) on days one and seven than that of delayed-release omeprazole (range, 1.7-2.3 hours) on day one (Table 26) and with a repeated administration (range, 1.4-1.8 hours) on day seven (Table 26). (Data from Santarus.)

Approximately 95% of omeprazole is protein-bound. In healthy subjects, its plasma half-life is about one hour (range, 0.4-3.2 hours) and the plasma clearance averages between 500 and 600 ml/ minute. Most of the omeprazole (77%) is excreted as metabolites in the urine, and the remainder is eliminated in the feces.


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