Rabeprazole Sodium DR (Page 4 of 7)

12. Clinical Pharmacology

12.1 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.

12.2 Pharmacodynamics

Antisecretory Activity

The antisecretory effect begins within one hour after oral administration of 20 mg rabeprazole sodium delayed-release tablets. The median inhibitory effect of rabeprazole on 24-hour gastric acidity is 88% of maximal after the first dose. A 20 mg dose of rabeprazole sodium delayed-release tablets 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 to 2 hours) reflects the sustained inactivation of the H+, K+ATPase.

Table 3: Gastric Acid Parameters: Rabeprazole sodium delayed-release tablets versus Placebo After 7 Days of Once Daily Dosing

Parameter Rabeprazole sodium delayed-release tablets(20 mg once daily) Placebo
Basal Acid Output (mmol/hr) 0.4* 2.8
Stimulated Acid Output (mmol/hr) 0.6* 13.3
% Time Gastric pH>3 65* 10

*(p<0.01 versus placebo)

Compared to placebo, 10 mg, 20 mg, and 40 mg of rabeprazole sodium delayed-release tablets, 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.

Table 4: AUC Acidity (Mmol•Hr/L): Rabeprazole sodium delayed-release tablets versus Placebo on Day 7 of Once Daily Dosing (Mean±SD)

AUC interval (hrs) Rabeprazole sodium delayed-release tablets
10 mg (N=24) 20 mg (N=24) 40 mg (N=24) Placebo (N=24)
08:00 to 13:00 19.6±21.5 * 12.9±23* 7.6±14.7* 91.1±39.7
13:00 to 19:00 5.6±9.7* 8.3±29.8* 1.3±5.2* 95.5±48.7
19:00 to 22:00 0.1±0.1* 0.1±0.06* 0.0±0.02* 11.9±12.5
22:00 to 08:00 129.2±84* 109.6±67.2* 76.9±58.4* 479.9±165
AUC 0-24 hours 155.5±90.6* 130.9±81* 85.8±64.3* 678.5±216

*(p<0.001 versus placebo)

After administration of 20 mg rabeprazole sodium delayed-release tablets once daily for eight days, the mean percent of time that gastric pH greater than 3 or gastric pH greater than 4 after a single dose (Day 1) and multiple doses (Day 8) was significantly greater than placebo (see table below). The decrease in gastric acidity and the increase in gastric pH observed with 20 mg rabeprazole sodium delayed-release tablets administered once daily for eight days were compared to the same parameters for placebo, as illustrated below:

Table 5: Gastric Acid Parameters rabeprazole sodium delayed-release tablets Once Daily Dosing versus Placebo on Day 1 and Day 8

Parameter Rabeprazole sodium delayed-release tablets 20 mg once daily Placebo
Day 1 Day 8 Day 1 Day 8
Mean AUC0-24 Acidity 340.8* 176.9* 925.5 862.4
Median trough pH (23-hr)a 3.77 3.51 1.27 1.38
% Time Gastric pH greater than 3b 54.6* 68.7* 19.1 21.7
% Time Gastric pH greater than 4b 44.1* 60.3* 7.6 11.0

a No inferential statistics conducted for this parameter.

b Gastric pH was measured every hour over a 24-hour period.

* (p<0.001 versus placebo)

Effects on Esophageal Acid Exposure

In patients with GERD and moderate to severe esophageal acid exposure, a dose of 20 mg and 40 mg per day of rabeprazole sodium delayed-release tablets decreased 24-hour esophageal acid exposure. After seven days of treatment, the percentage of time that the esophageal pH was less than 4 decreased from baselines of 24.7% for 20 mg and 23.7% for 40 mg, to 5.1% and 2.0%, respectively. Normalization of 24-hour intraesophageal acid exposure was correlated to gastric pH greater than 4 for at least 35% of the 24-hour period; this level was achieved in 90% of subjects receiving rabeprazole sodium delayed-release tablets 20 mg and in 100% of subjects receiving rabeprazole sodium delayed-release tablets 40 mg. With rabeprazole sodium delayed-release tablets 20 mg and 40 mg per day, significant effects on gastric and esophageal pH were noted after one day of treatment, and more pronounced after seven days of treatment.

Effects on Serum Gastrin

The median fasting gastrin level increased in a dose-related manner in patients treated once daily with rabeprazole sodium delayed-release tablets for up to eight weeks for ulcerative or erosive esophagitis and in patients treated for up to 52 weeks to prevent recurrence of disease. The group median values stayed within the normal range.

In a group of subjects treated with 20 mg rabeprazole sodium delayed-release tablets for 4 weeks a doubling of mean serum gastrin concentrations was observed. Approximately 35% of these treated subjects developed serum gastrin concentrations above the upper limit of normal.

Effects on Enterochromaffin-like (ECL) Cells

Increased serum gastrin secondary to antisecretory agents stimulates proliferation of gastric ECL cells which, over time, may result in ECL cell hyperplasia in rats and mice and gastric carcinoids in rats, especially in females [see NONCLINICAL TOXICOLOGY (13.1)].

In over 400 patients treated with rabeprazole sodium delayed-release tablets (10 or 20 mg) once daily for up to one year, the incidence of ECL cell hyperplasia increased with time and dose, which is consistent with the pharmacological action of the proton pump inhibitor. No patient developed the adenomatoid, dysplastic or neoplastic changes of ECL cells in the gastric mucosa. No patient developed the carcinoid tumors observed in rats.

Endocrine Effects

Studies in humans for up to one year have not revealed clinically significant effects on the endocrine system. In healthy male subjects treated with rabeprazole sodium delayed-release tablets for 13 days, no clinically relevant changes have been detected in the following endocrine parameters examined: 17 β-estradiol, thyroid stimulating hormone, tri-iodothyronine, thyroxine, thyroxine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteotrophic hormone, prolactin, somatotrophic hormone, dehydroepiandrosterone, cortisol-binding globulin, and urinary 6β-hydroxycortisol, serum testosterone and circadian cortisol profile.

Other Effects

In humans treated with rabeprazole sodium delayed-release tablets for up to one year, no systemic effects have been observed on the central nervous, lymphoid, hematopoietic, renal, hepatic, cardiovascular, or respiratory systems. No data are available on long-term treatment with rabeprazole sodium delayed-release tablets and ocular effects.

12.3 Pharmacokinetics

After oral administration of 20 mg rabeprazole sodium delayed-release tablets, peak plasma concentrations (Cmax) of rabeprazole occur over a range of 2 to 5 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 is not altered by multiple dosing.

Absorption

Absolute bioavailability for a 20 mg oral tablet of rabeprazole (compared to intravenous administration) is approximately 52%. When rabeprazole sodium delayed-release tablets are administered with a high fat meal, Tmax is variable, which concomitant food intake may delay the absorption up to 4 hours or longer. However, the Cmax and the extent of rabeprazole absorption (AUC) are not significantly altered. Thus rabeprazole sodium delayed-release tablets may be taken without regard to timing of meals.

Distribution

Rabeprazole is 96.3% bound to human plasma proteins.

Elimination

Metabolism: Rabeprazole is extensively metabolized. A significant portion of rabeprazole is metabolized via systemic nonenzymatic reduction to a thioether compound. Rabeprazole is also metabolized to sulphone and desmethyl compounds via cytochrome P450 in the liver. 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 metabolized in the liver primarily by cytochromes P450 3A (CYP3A) to a sulphone metabolite and cytochrome P450 2C19 (CYP2C19) to desmethyl rabeprazole. CYP2C19 exhibits a known genetic polymorphism due to its deficiency in some sub-populations (e.g., 3 to 5% of Caucasians and 17 to 20% of Asians). Rabeprazole metabolism is slow in these sub-populations, therefore, they are referred to as poor metabolizers of the drug.

Excretion: Following a single 20 mg oral dose of 14C-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.

Specific Populations

Geriatric Patients: In 20 healthy elderly subjects administered 20 mg rabeprazole sodium delayed-Release tablets 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 Use in Specific Population (8.5)].

Pediatric Patients: The pharmacokinetics of rabeprazole was studied in 12 adolescent patients with GERD 12 to 16 years of age, in a multicenter study. Patients received 20 mg rabeprazole sodium delayed-release tablets once daily for five or seven days. An approximate 40% increase in rabeprazole exposure was noted following 5 to 7 days of dosing compared with the exposure after 1 day dosing. Pharmacokinetic parameters in adolescent patients with GERD 12 to 16 years of age were within the range observed in healthy adult subjects.

Male and Female Patients and Racial or Ethnic Groups: 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 to 60% greater than values derived from pooled data from healthy men in the United States.

Patients with Renal Impairment: 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 dose of rabeprazole sodium delayed-release tablets when compared to 10 healthy subjects.

Patients with Hepatic Impairment: In a single dose study of 10 patients with mild to moderate hepatic impairment (Child-Pugh Class A and B, respectively) who were administered a single 20 mg dose of rabeprazole sodium delayed-release tablets, 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 sodium delayed-release tablets 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 (Child-Pugh Class C) [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Combined Administration with Antimicrobials: Sixteen healthy subjects genotyped as extensive metabolizers with respect to CYP2C19 were given 20 mg rabeprazole sodium delayed-release tablets, 1000 mg amoxicillin, 500 mg clarithromycin, or all 3 drugs in a four-way crossover study. Each of the four regimens was administered twice daily for 6 days. The AUC and Cmax for clarithromycin and amoxicillin were not different following combined administration compared to values following single administration. However, the rabeprazole AUC and Cmax increased by 11% and 34%, respectively, following combined administration. The AUC and Cmax for 14-hydroxyclarithromycin (active metabolite of clarithromycin) also increased by 42% and 46%, respectively. This increase in exposure to rabeprazole and 14-hydroxyclarithromycin is not expected to produce safety concerns.

Effects of Other Drugs on Rabeprazole

Antacids: Co-administration of rabeprazole sodium delayed-release tablets and antacids produced no clinically relevant changes in plasma rabeprazole concentrations.

Effects of Rabeprazole on Other Drugs

Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as theophylline (CYP1A2) given as single oral doses, diazepam (CYP2C9 and CYP3A4) as a single intravenous dose, and phenytoin (CYP2C9 and CYP2C19) given as a single intravenous dose (with supplemental oral dosing). Steady state interactions of rabeprazole and other drugs metabolized by this enzyme system have not been studied in patients.

Clopidogrel: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. A study of healthy subjects including CYP2C19 extensive and intermediate metabolizers receiving once daily administration of clopidogrel 75 mg concomitantly with placebo or with 20 mg rabeprazole sodium delayed-release tablets (n=36), for 7 days was conducted. The mean AUC of the active metabolite of clopidogrel was reduced by approximately 12% (mean AUC ratio was 88%, with 90% CI of 81.7 to 95.5%) when rabeprazole sodium delayed-release tablets were coadministered compared to administration of clopidogrel with placebo [see Drug Interactions (7)].

Digoxin: In healthy adult subjects (n=16), co-administration of 20 mg rabeprazole sodium delayed-release tablets with 2.5 mg once daily doses of digoxin at steady state resulted in approximately 29% and 19% increase in mean Cmax and AUC(0-24) of digoxin [see Drug Interactions (7)].

Ketoconazole: In healthy adult subjects (n=19), co-administration of 20 mg rabeprazole sodium delayed-release tablets at steady state with a single 400 mg oral dose ketoconazole resulted in approximately an average of 31% reduction in both Cmax and AUC(0-inf) of ketoconazole [see Drug Interactions (7)].

Cyclosporine: In vitro incubations employing human liver microsomes indicated that rabeprazole inhibited cyclosporine metabolism with an IC50 of 62 micromolar, a concentration that is over 50 times higher than the Cmax in healthy volunteers following 14 days of dosing with 20 mg of rabeprazole sodium delayed-release tablets. This degree of inhibition is similar to that by omeprazole at equivalent concentrations.

12.4 Microbiology

The following in vitro data are available but the clinical significance is unknown.

Rabeprazole sodium, amoxicillin and clarithromycin as a three drug regimen has been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections [see Indications and Usage (1), Clinical Studies (14.5)].

Helicobacter pylori

Susceptibility testing of H. pylori isolates was performed for amoxicillin and clarithromycin using agar dilution methodology1, and minimum inhibitory concentrations (MICs) were determined.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.

Incidence of Antibiotic-Resistant Organisms Among Clinical Isolates

Pretreatment Resistance: Clarithromycin pretreatment resistance rate (MIC ≥1 mcg/mL) to H. pylori was 9% (51/560) at baseline in all treatment groups combined. Greater than 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤0.25 mcg/mL) to amoxicillin at baseline. Two patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mcg/mL.

For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

Table 6: Clarithromycin Susceptibility Test Results and Clinical/ Bacteriologic Outcomesa for a Three Drug Regimen (rabeprazole sodium delayed-release tablets 20 mg Twice Daily, Amoxicillin 1000 mg Twice Daily, and Clarithromycin 500 mg Twice Daily for 7 or 10 Days)

Days of RAC Therapy Clarithromycin Pretreatment Results Total Number H. pylori Negative (Eradicated) H. pylori Positive (Persistent) Post-Treatment Susceptibility Results
Sb Ib Rb No MIC
7 Susceptibleb 129 103 2 0 1 23
7 Intermediateb 0 0 0 0 0 0
7 Resistantb 16 5 2 1 4 4
10 Susceptibleb 133 111 3 1 2 16
10 Intermediateb 0 0 0 0 0 0
10 Resistantb 9 1 0 0 5 3

a Includes only patients with pretreatment and post-treatment clarithromycin susceptibility test results.

b Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC = 0.5 mcg /mL, Resistant (R) MIC ≥ 1 mcg/mL

Patients with persistent H. pylori infection following rabeprazole, amoxicillin, and clarithromycin therapy will likely have clarithromycin resistant clinical isolates. Therefore, clarithromycin susceptibility testing should be done when possible. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the U.S. multicenter study, greater than 99% (558/560) of patients had H. pylori isolates which were considered to be susceptible (MIC ≤0.25 mcg/mL) to amoxicillin at baseline. The other 2 patients had baseline H. pylori isolates with an amoxicillin MIC of 0.5 mcg/mL, and both isolates were clarithromycin-resistant at baseline; in one case the H. pylori was eradicated. In the 7-and 10-day treatment groups 75% (107/145) and 79% (112/142), respectively, of the patients who had pretreatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of

H. pylori. No patients developed amoxicillin-resistant H. pylori during therapy.

12.5 Pharmacogenomics

In a clinical study in evaluating rabeprazole sodium delayed-release tablets in Japanese adult patients categorized by CYP2C19 genotype (n=6 per genotype category), gastric acid suppression was higher in poor metabolizers as compared to extensive metabolizers. This could be due to higher rabeprazole plasma levels in poor metabolizers. The clinical relevance of this is not known. Whether or not interactions of rabeprazole sodium with other drugs metabolized by CYP2C19 would be different between extensive metabolizers and poor metabolizers has not been studied.

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