CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism

ACIPHEX™ delayed-release tablets are enteric-coated to allow rabeprazole sodium, which is acid labile, to pass through the stomach relatively intact. After oral administration of 20 mg ACIPHEX TM , peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2.0 to 5.0 hours (Tmax). The rabeprazole Cmax and AUC are linear over an oral dose range of 10 mg to 40 mg. There is no appreciable accumulation when doses of 10 mg to 40 mg are administered every 24 hours; the pharmacokinetics of rabeprazole are not altered by multiple dosing. The plasma half-life ranges from 1 to 2 hours.

Absorption: Following oral administration of 20 mg, rabeprazole is absorbed and can be detected in plasma by 1 hour. Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%.

The effects of food on the absorption of rabeprazole have not been evaluated.

Distribution: Rabeprazole is 96.3% bound to human plasma proteins.

Metabolism: Rabeprazole is extensively metabolized. The thioether and sulphone are the primary metabolites measured in human plasma. These metabolites were not observed to have significant antisecretory activity. In vitro studies have demonstrated that rabeprazole is primarily metabolized in the liver by cytochromes P450 3A (sulphone metabolite) and 2C19 (desmethyl rabeprazole). The thioether metabolite is formed by reduction of rabeprazole.

Elimination: Following a single 20 mg oral dose of 14 C-labeled rabeprazole, approximately 90% of the drug was eliminated in the urine, primarily as thioether carboxylic acid; its glucuronide, and mercapturic acid metabolites. The remainder of the dose was recovered in the feces. Total recovery of radioactivity was 99.8%. No unchanged rabeprazole was recovered in the urine or feces.

Special Populations

Geriatric: In 20 healthy elderly subjects administered 20 mg rabeprazole once daily for seven days, AUC values approximately doubled and the Cmax increased by 60% compared to values in a parallel younger control group. There was no evidence of drug accumulation after once daily administration. (see PRECAUTIONS).

Pediatric: The pharmacokinetics of rabeprazole in pediatric patients under the age of 18 years have not been studied.

Gender and Race: In analyses adjusted for body mass and height, rabeprazole pharmacokinetics showed no clinically significant differences between male and female subjects. In studies that used different formulations of rabeprazole, AUC0-¥ values for healthy Japanese men were approximately 50-60% greater than values derived from pooled data from healthy men in the United States.

Renal Disease: In 10 patients with stable end-stage renal disease requiring maintenance hemodialysis (creatinine clearance £5 mL/min/1.73 m2), no clinically significant differences were observed in the pharmacokinetics of rabeprazole after a single 20 mg oral dose when compared to 10 healthy volunteers.

Hepatic Disease: In a single dose study of 10 patients with chronic mild to moderate compensated cirrhosis of the liver who were administered a 20 mg dose of rabeprazole, AUC0-24 was approximately doubled, the elimination half-life was 2- to 3-fold higher, and total body clearance was decreased to less than half compared to values in healthy men.

In a multiple dose study of 12 patients with mild to moderate hepatic impairment administered 20 mg rabeprazole once daily for eight days, AUC0-¥ and Cmax values increased approximately 20% compared to values in healthy age-and gender-matched subjects. These increases were not statistically significant.

No information exists on rabeprazole disposition in patients with severe hepatic impairment. Please refer to the DOSAGE AND ADMINISTRATION section for information on dosage adjustment in patients with hepatic impairment.

PHARMACODYNAMICS

Mechanism of Action

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+ , K+ ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.

In gastric parietal cells, rabeprazole is protonated, accumulates, and is transformed to an active sulfenamide. When studied in vitro, rabeprazole is chemically activated at pH 1.2 with a half-life of 78 seconds. It inhibits acid transport in porcine gastric vesicles with a half-life of 90 seconds.

Antisecretory Activity

The anti-secretory effect begins within one hour after oral administration of 20 mg ACIPHEXTM. The median inhibitory effect of ACIPHEX™ on 24 hour gastric acidity is 88% of maximal after the first dose. ACIPHEXTM 20 mg inhibits basal and peptone meal-stimulated acid secretion versus placebo by 86% and 95%, respectively, and increases the percent of a 24-hour period that the gastric pH>3 from 10% to 65% (see table below). This relatively prolonged pharmacodynamic action compared to the short pharmacokinetic half-life (1-2 hours) reflects the sustained inactivation of the H+ , K + ATPase.

Gastric Acid Parameters

ACIPHEX™ versus Placebo After 7 Days of Once Daily Dosing

Compared to placebo, ACIPHEXTM, 10 mg, 20 mg, and 40 mg, administered once daily for 7 days significantly decreased intragastric acidity with all doses for each of four meal-related intervals and the 24-hour time period overall. In this study, there were no statistically significant differences between doses; however, there was a significant dose-related decrease in intragastric acidity. The ability of rabeprazole to cause a dose-related decrease in mean intragastric acidity is illustrated below.

AUD Acidity (mmol-hr/L)

ACIPHEX™ versus Placebo on Day 7 of Once Daily Dosing (mean ±SD)

In addition, there was a statistically significant difference in favor of the ACIPHEXTM 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (£0.026). All ACIPHEXTM groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p£0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all ACIPHEXTM groups when compared to placebo at both Weeks 4 and 8 (p£0.007).

In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, ACIPHEXTM was statistically superior to ranitidine with respect to the percentage of patients healed at endoscopy after four and eight weeks of treatment (see table below):

Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD)

Percentage of Patients Healed

* (p <0.001 vs ranitidine)

ACIPHEXTM 20 mg once daily was significantly more effective than ranitidine 150 mg QID in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (£ 0.001). ACIPHEXTM 20 mg once daily was also more effective in complete resolution of daytime heartburn (£0.025), and night time heartburn (p£0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.

Long-term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance)

The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric anti-secretory therapy was assessed in two U.S. multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of ACIPHEX TM QD or placebo. As demonstrated in the tables below, ACIPHEXTM was significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks:

Long-Term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease

(GERD Maintenance) Percent of Patients in Endoscopic Remission

Long-Term Maintenance of Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD Maintenance):

Percent of Patients Without Relapse in Heartburn Frequency and Daytime and Nighttime

Heartburn Severity at Week 52

*p£0.001 vs. placebo
0.001< p < 0.05 vs. placebo

Healing of Duodenal Ulcers

In a U.S. randomized, double-blind, multi-center study assessing the effectiveness of 20 mg and 40 mg of ACIPHEXTM QD versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. ACIPHEXTM was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:

Healing of Duodenal Ulcers

Percentage of Patients Healed

At Weeks 2 and 4, significantly more patients in the ACIPHEXTM 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p£0.018), daytime pain severity (p£0.023), and nighttime pain severity (p£0.035) compared with placebo patients. The only exception was the ACIPHEXTM 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both ACIPHEXTM groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both ACIPHEXTM groups compared to placebo at Weeks 2 and 4 (p<0.001).

An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg ACIPHEXTM QD with 20 mg omeprazole QD. The study was designed to provide at least 80% power to exclude a difference of at least 10% between ACIPHEXTM and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, ACIPHEXTM was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

Healing of Duodenal Ulcers

Percentage of Patients Healed

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

Twelve patients with idiopathic gastric hypersecretion or Zollinger-Ellison syndrome have been treated successfully with ACIPHEXTM at doses from 20 to 120 mg for up to 12 months. ACIPHEXTM produced satisfactory inhibition of gastric acid secretion in all patients and complete resolution of signs and symptoms of acid-peptic disease where present. ACIPHEXTM also prevented recurrence of gastric hypersecretion and manifestations of acid-peptic disease in all patients. The high doses of ACIPHEXTM used to treat this small cohort of patients with gastric hypersecretion were not associated with drug-related adverse effects.