Background: Rapid and consistent acid suppression on the first day of dosing may be important in treating acid-related disorders.
Aim: To compare the antisecretory activity and onset of action of single doses of rabeprazole, lansoprazole, pantoprazole, omeprazole capsule, omeprazole multiple unit pellet system (MUPS) tablet and placebo in healthy Helicobacter pylori-negative subjects.
Methods: This cross-over, double-blind, randomized study was performed in 18 H. pylori-negative subjects. Twenty-four-hour intragastric pH monitoring was performed on the day of treatment (once-daily dose of rabeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, omeprazole capsule 20 mg, omeprazole MUPS tablet 20 mg or placebo).
Results: The intragastric pH (3.4) and time at pH > 4 during the 24 h post-dose (8.0 h) were significantly greater with rabeprazole than with lansoprazole, pantoprazole, omeprazole capsule, omeprazole MUPS tablet or placebo (P ≤ 0.04 for rabeprazole vs. the others). Daytime and night-time pH values were higher with rabeprazole and lansoprazole than with pantoprazole, omeprazole capsule and omeprazole MUPS tablet (P ≤ 0.04).
Conclusion: Rabeprazole was the most potent acid inhibitor of all the proton pump inhibitors tested during the first day of dosing.
The onset of action, degree and duration of acid suppression with proton pump inhibitors are relevant to the treatment of acid-related disorders.1,2 In gastro-oesophageal reflux disease, rapid acid suppression is important for effective pain relief at the onset of treatment.3 Ideally, the first dose of a proton pump inhibitor should lead to strong and fast acid inhibition. Rapid acid control may also be of clinical advantage in Helicobacter pylori treatment regimens with acid-sensitive antibiotics, such as clarithromycin and amoxicillin.4 Data obtained through in vitro studies suggest that proton pump inhibitors may differ with respect to the rate of inhibition of gastric H+, K+-ATPase.5,6 Acid inhibition in vitro is fastest with rabeprazole, moderate with omeprazole and lansoprazole, and slowest with pantoprazole. Clinical studies have confirmed differences between the proton pump inhibitors with respect to the time to onset of antisecretory action on the first day of treatment, as well as the degree and consistency of acid control. At one end of the spectrum, omeprazole has a very weak first-day inhibitory effect when compared with esomeprazole,7 lansoprazole,8–12 pantoprazole13,14 and rabeprazole.15 At the other end of the spectrum, lansoprazole16,17 and rabeprazole15,18 show very strong first-day acid inhibition. No study has compared directly all the available proton pump inhibitors with regard to their ability to suppress acid on the first day of dosing.
Thus, the objective of this study was to compare the degree and rate of onset of antisecretory activity after a single dose of rabeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, omeprazole capsule 20 mg and omeprazole multiple unit pellet system (MUPS) tablet 20 mg in healthy H. pylori-negative subjects.
Materials and methods
Eighteen H. pylori-negative subjects (nine men and nine women; median age, 26.5 years; range, 18–48 years) were enrolled in the study. Subjects with a history of peptic ulcer disease, non-ulcer dyspepsia or clinical evidence of liver, pancreatic or renal disease were excluded from the study. Other exclusion criteria included any abnormalities in routine blood biochemistry, positive tests for human immunodeficiency virus, hepatitis B surface antigen or anti-hepatitis C virus and positive pregnancy tests in female volunteers. Systemic antibiotics, bismuth-containing compounds, antacids and acid-suppressant drugs, such as proton pump inhibitors, H2 antagonists and antimuscarinics, were not permitted in the 28 days prior to the start of the study. None of the volunteers were taking any medication other than oral contraceptives during the study. The study was conducted under the provisions of the Declaration of Helsinki and in accordance with the International Congress on Harmonisation Consolidated Guideline on Good Clinical Practice. The protocol was approved by the local ethics committee and by the International Office for Drug Control in Berne, Switzerland.
Subjects with a negative 13C-urea breath test and a serology-negative enzyme-linked immunosorbent assay (Roche, Basel, Switzerland) for H. pylori infection were included in the study. Each subject received a single dose of each study treatment in a randomized, modified double-blind, cross-over fashion, with a 14–28-day washout period between each administration. The study treatments were rabeprazole 20 mg, lansoprazole 30 mg, pantoprazole 40 mg, omeprazole capsule 20 mg, omeprazole MUPS tablet 20 mg and placebo. Twenty-four-hour intragastric pH monitoring was performed on the treatment days. Subjects were questioned about adverse events on the day following drug administration. In addition, 5–10 days after the last treatment visit, all subjects were contacted by telephone for adverse event follow-up.
Twenty-four-hour pH monitoring
Subjects presented at the clinic at 07.30 h after an overnight fast. Twenty-four-hour ambulatory pH measurements started at 08.00 h and ended at 08.00 h the next day. After the supervised administration of the study medication at 08.30 h, the volunteers left the hospital. They were instructed to eat standardized meals at 10.00 h, 13.00 h and 19.00 h, and to drink still mineral water ad libitum; other beverages were not allowed. Smokers were requested to refrain from smoking during the recording period. During pH monitoring sessions, volunteers were instructed to be upright during the day (08.00–22.30 h) and to lie down during the night (22.30–06.30 h).
The intragastric pH was measured using a glass pH electrode with a built-in Ag/AgCl reference electrode (MIC, Ingold, 440-M3, Urdorf, Switzerland) connected to a portable data logger (GastrograpH III, MIC, Basel, Switzerland). The pH electrode was calibrated before and after each recording using standard buffer solutions of pH 1.68 and pH 7.00 (Ingold AG, Urdorf, Switzerland). The electrode was introduced intranasally after topical application of a local anaesthetic gel (xylocaine 2%) and positioned under fluoroscopic control in the gastric corpus, 5 cm distal to the cardia. At the end of each recording, the position of the electrode was re-checked fluoroscopically. Data were transferred to a personal computer (Vectra VE, Hewlett-Packard, HP-PC, Palo Alto, CA, USA) for analysis and permanent storage on a floppy disk. Recordings were evaluated only if the pH electrode had not been displaced and if the 24-h drift of the electrode did not exceed 0.2 pH units.
Standardized meals for each pH monitoring session were prepared by the hospital in accordance with the dietician to ensure stable nutrient composition and caloric content. To exclude the buffering effect of a high-protein diet on the intragastric acidity during the first 6 h of the pH recording, the nutrient composition of breakfast (109 g carbohydrates, 7 g proteins, 4 g fat) and lunch (74 g carbohydrates, 27 g proteins, 32 g fat) was based mainly on carbohydrates.19 In addition, volunteers were instructed to take breakfast 1.5 h after administration of the study treatment (at 10.00 h) to prevent the effect of food on the pharmacokinetics of the proton pump inhibitors.20–22
Each volunteer received a single dose of rabeprazole tablet 20 mg (Eisai Ltd, London, UK), lansoprazole capsule 30 mg (Takeda Chemical Industries Ltd, Osaka, Japan), pantoprazole tablet 40 mg (Knoll, Karachi, Pakistan), omeprazole capsule 20 mg (AstraZeneca, Sodertalje, Sweden), omeprazole MUPS tablet 20 mg (AstraZeneca, Sodertalje, Sweden) and placebo. As the five study treatments were produced in three different galenic formulations, the standard double-blind design was amended to ensure adequate blindness of the investigators and subjects. The random plan was established by an independent clinical technician who otherwise did not participate in the study. Drugs were stored in a locked room. Study treatments were administered in the absence of the investigator by a clinical nurse who had no contact with the volunteers other than drug administration. The drug was administered directly into the mouth, in a darkened room, to ensure that subjects could not visually identify the study treatment they were receiving.
Diagnosis of H. pylori infection
13C-urea breath tests were performed at enrolment, as described previously.23 Fasting blood samples from each subject were collected for the determination of specific immunoglobulin G anti-H. pylori antibodies. H. pylori antibodies were measured by an enzyme-linked immunosorbent assay. Subjects were included in the study only if both tests were negative.
Data analysis and statistical evaluation
Median pH values for the following pre-defined time periods were calculated: non-drug period (baseline measurement obtained prior to drug administration, 08.00–08.30 h), post-dose period (08.30–08.00 h), daytime period (08.30–22.30 h) and night-time period (22.30–06.30 h). The median time spent above pH 3 and pH 4 during the post-dose period (08.30–08.00 h) and the proportions of subjects who reached pH ≥ 3 and pH ≥ 4 sustained for ≥ 3 h were calculated for each study treatment.
The median pH values for 15-min intervals during the first 6 h of pH recording (including the 30-min non-drug period and the 5.5 h of the post-dose period) were used for the calculation of the time to onset of antisecretory action. The time to onset of antisecretory activity was defined as the time to onset of the initial pH rise (≥ 1 unit change in pH compared with the non-drug period). All data were given as group median values (10–90 centiles).
The assumption of normality of the data was verified by the Shapiro–Wilk test. Non-parametric methods were used when the above method did not recover normality. The median pH values and median percentage of time spent at pH 3 and pH 4 were analysed using the Friedman repeated measures analysis of variance on ranks. Pairwise comparisons were performed using the Wilcoxon signed rank test for paired data. Categorical variables were compared using chi-squared statistics (Pearson's chi-squared test and Fisher's exact test). For all tests, significance was considered at a 5% probability level. No assessment of carry-over was performed. The 14–28-day washout between each single dose was sufficient to avoid this problem on the basis of the pharmacokinetics of the study treatments. No adjustment was made to account for multiple testing, as this study was exploratory in nature and was designed to generate hypotheses for future studies.
Eighteen volunteers (nine men and nine women; mean age, 26.5 years; range, 18–48 years) completed the study. In one subject, the evaluation of pH data revealed hypochlorhydria (median 24-h intragastric pH of 3.9 during the administration of placebo). This subject underwent upper gastrointestinal endoscopy with gastric and duodenal biopsies. Subsequent histopathological examination of the biopsies showed atrophic lymphocytic gastritis in the absence of H. pylori infection and subtotal atrophy of the duodenal mucosa indicative of coeliac disease. Data from this subject were excluded from the analysis. No adverse events related to the study medication were reported during the course of the study.
Acid suppression during the first 23.5 h of dosing
Median intragastric pH. The 24-h intragastric pH profiles obtained after a single dose of each medication are shown in Figure 1. All proton pump inhibitors significantly increased the intragastric pH when compared with placebo during the post-dose period and during all daytime periods (Table 1). Rabeprazole, lansoprazole and pantoprazole, but not omeprazole capsule and omeprazole MUPS tablet, maintained their acid-inhibiting effect during the night when compared with placebo (Table 1).
Table 1. Median pH monitoring values before and on the first day of each proton pump inhibitor treatment. Values in parentheses are 10–90% confidence intervals
The median intragastric pH values during the post-dose period were higher with rabeprazole than with lansoprazole, pantoprazole, omeprazole capsule and omeprazole MUPS tablet (3.4 vs. 2.9, 2.2, 1.9 and 1.8, respectively; P ≤ 0.03). The median pH values with rabeprazole were higher than those with pantoprazole, omeprazole capsule or omeprazole MUPS tablet during both daytime and night-time periods (daytime: 3.6 vs. 2.2, 1.8 and 2.1, respectively; night-time: 2.3 vs. 1.6, 1.6 and 1.5, respectively) (Table 1). Lansoprazole produced a higher intragastric pH when compared with pantoprazole, omeprazole capsule and omeprazole MUPS tablet during the day (3.3 vs. 2.2, 1.8 and 2.1, respectively; P ≤ 0.01). However, this difference disappeared during the night (2.1 vs. 1.6, 1.6 and 1.5, respectively; P > 0.05).
Time at intragastric pH > 3 and pH > 4 during the post-dose period. Compared with placebo, all the proton pump inhibitors significantly increased the amount of time at intragastric pH > 3 and pH > 4 (Table 2). The intragastric pH was maintained above pH 3 for longer periods with rabeprazole when compared with pantoprazole, omeprazole capsule and omeprazole MUPS tablet (13.1 h vs. 6.9, 5.8 and 5.7 h, respectively; P < 0.005). Rabeprazole was superior to all other proton pump inhibitors tested (lansoprazole, pantoprazole, omeprazole capsule and omeprazole MUPS tablet) in controlling the intragastric pH above the critical threshold of pH 4 (8.0 h vs. 7.4, 4.9, 2.9 and 3.0 h, respectively; P ≤ 0.003) (Table 2). Lansoprazole sustained the intragastric pH at 3 and 4 for a longer period of time (11.2 and 7.4 h) than pantoprazole (6.9 and 4.9 h) or omeprazole capsule (5.8 and 2.9 h) (P < 0.02). There were no differences between pantoprazole, omeprazole capsule and omeprazole MUPS tablet with respect to the amount of time at intragastric pH > 3 and pH > 4.
Table 2. Median time (hours) at pH > 3 and pH > 4. Values in parentheses are 10–90% confidence intervals
pH ≥ 3 and pH ≥ 4 sustained for ≥ 3 h. A number of subjects from each of the five active treatment groups failed to reach pH ≥ 3 and pH ≥ 4 for more than 3 h. Of the 17 subjects analysed, 16 on rabeprazole and 16 on lansoprazole (94%) reached and sustained pH 3 for ≥ 3 h. This was significantly more than the respective proportions of subjects on pantoprazole (9/17), omeprazole capsule (3/17) and omeprazole MUPS tablet (7/17) (P ≤ 0.01).
The proportion of subjects who reached and sustained pH ≥ 4 for ≥ 3 h was highest with rabeprazole (13/17), and significantly greater than with lansoprazole (8/17), pantoprazole (6/17), omeprazole capsule (3/17) and omeprazole MUPS tablet (5/17) (P ≤ 0.02).
Onset of antisecretory action
The onset of antisecretory action for all the active study drugs occurred in the majority of subjects within 2 h of drug administration. The onset time of antisecretory action, or the first evidence of a statistically significant difference in the median pH values compared with the non-drug period (at 15-min intervals during the first 6 h), was 1 h for lansoprazole, 1.25 h for omeprazole MUPS tablet, 1.5 h for omeprazole capsule, 1.75 h for pantoprazole and 1.75 h for rabeprazole (P = 0.6).
The present study demonstrates that rabeprazole is a more potent proton pump inhibitor than lansoprazole, pantoprazole, omeprazole capsule and omeprazole MUPS tablet on the first day of treatment. Rabeprazole produced a higher median intragastric pH than the other proton pump inhibitors tested throughout the entire post-dose period. The high intragastric pH with rabeprazole was maintained for a longer period of time than with lansoprazole, pantoprazole or omeprazole. Rabeprazole maintained an intragastric pH above the critical healing threshold of pH 4 for a longer period of time, and did so in more subjects in comparison with lansoprazole, pantoprazole and omeprazole. Rabeprazole, lansoprazole and pantoprazole, but not omeprazole capsule and omeprazole MUPS tablet, maintained their acid-inhibiting effect during the night when compared with placebo. Thus, the greater acid suppression demonstrated by rabeprazole on the first day of dosing, when compared with all other proton pump inhibitors tested, provides evidence of the fast onset of antisecretory activity with this drug.
Several mechanisms may explain the superior efficacy of rabeprazole on the first day of dosing. It has been suggested that the acid stability (pKa) of a proton pump inhibitor is a main factor in the determination of its acid-inhibitory potency.6 The acid stability of a proton pump inhibitor determines the rate of accumulation of the pro-drug in the acidic secretory canaliculus of the parietal cell and the rate of acid-activated formation of an active sulphenamide.5,6In vitro studies have shown that acid inhibition is fastest with rabeprazole, which is a less acid-stable proton pump inhibitor, slower with omeprazole and lansoprazole, and slowest with pantoprazole, which is the most acid stable of all the proton pump inhibitors.6 The majority of parietal cells have pH 1, but a proportion of cells may have a value as high as pH 3, depending on the degree of stimulation and the age of the parietal cell itself. Therefore, whereas the proton pump inhibitors are equipotent in highly acidic conditions, rabeprazole may be as much as 10 times more potent than the other proton pump inhibitors tested in the mildly acidic conditions (pH ∼ 3) occurring in the acid space of non-stimulated or older parietal cells (G. Sachs, 2002, personal communication). Thus, rabeprazole may target a greater population of proton pumps than the other proton pump inhibitors, resulting in more rapid and greater acid suppression.
The potent antisecretory effect of rabeprazole on the first day of dosing, also observed in previous clinical studies, is consistent with the results obtained in in vitro studies.15 The onset of antisecretory action occurred 30–45 min later with rabeprazole, pantoprazole and omeprazole capsule than with lansoprazole and omeprazole MUPS tablet. However, as this difference was less than 1 h, it is probably of little, if any, clinical relevance. The differences in the onset of antisecretory action during the first 2 h following drug administration can be explained by the different rates of absorption of the pro-drugs into the blood. This rate of absorption is related to the galenic formulations used.24 In the present study, lansoprazole and omeprazole were administered in the form of hard gelatine capsules, whereas the omeprazole MUPS tablet contained individually enteric-coated pellets, and rabeprazole and pantoprazole were in the form of single-unit enteric-coated tablets. Absorption from enteric-coated tablet forms, which must first dissolve in the small intestine before absorption occurs, is delayed compared with that from small, individually coated, dosage forms.24
Acid secretion follows a circadian pattern, increasing over the evening hours and peaking after midnight.25 This phenomenon can be seen in Figure 1, in which the pH levels are lowest between midnight and 04.00 h for all treatment groups. Despite this physiological drop in pH, rabeprazole produced statistically significant acid suppression between 22.30 and 06.30 h compared with all the other proton pump inhibitors. Previous studies have shown that rabeprazole 20 mg significantly reduces night-time intragastric acidity compared with omeprazole 20 mg on day 1 of dosing.15 Studies comparing rabeprazole and esomeprazole have shown rabeprazole to produce greater or equivalent acid suppression on day 1, with rabeprazole demonstrating significant superiority at night.26 In a recently published, two-way cross-over study, rabeprazole 20 mg also produced significantly higher mean night-time intragastric pH and time at pH > 3 and pH > 4 than esomeprazole 20 mg.27
The significantly greater nocturnal acid suppression of rabeprazole, lansoprazole and pantoprazole on day 1 compared with omeprazole capsule and omeprazole MUPS tablet may be explained by their different pharmacokinetic properties. The maximum plasma concentration (Cmax) and the area under the concentration–time curve (AUC) are dose proportional for rabeprazole, lansoprazole and pantoprazole, and these values increase linearly. In contrast, the AUC for omeprazole and esomeprazole increases in a non-linear manner with repeat dosing. This pharmacokinetic stability means that rabeprazole, lansoprazole and pantoprazole will reach their full bioavailability on day 1 of dosing, whereas the bioavailability of omeprazole and esomeprazole increases over 5 days.28–32 Thus, the combination of rabeprazole's bioavailability, low acid stability and greater potency on the first day of dosing appears to maintain higher pH levels for longer periods of time during the daytime and night-time periods.
The findings obtained in the present study have several clinical implications for the management of gastro-oesophageal reflux disease and the treatment of H. pylori infection. A new approach based on symptom-driven, on-demand treatment with proton pump inhibitors is increasingly being employed in the long-term management of gastro-oesophageal reflux disease.33 An ideal proton pump inhibitor for on-demand therapy should achieve an effective control of intragastric, and hence intra-oesophageal, pH with consequent fast, sustained relief of reflux symptoms on the first day of dosing.3,34 This study has demonstrated that rabeprazole maintains an intragastric pH > 4 for a longer period and in more subjects when compared with the other proton pump inhibitors tested. These observations suggest that rabeprazole may be a potential candidate for on-demand treatment. In addition, recent data have suggested that rapid acid control with rabeprazole may be of clinical advantage in H. pylori treatment regimens with acid-sensitive antibiotics, such as clarithromycin and amoxicillin.35–37
In conclusion, this is the first study to show that rabeprazole provides more rapid and greater acid control than lansoprazole, pantoprazole, omeprazole capsule or omeprazole MUPS tablet throughout the first 24 h of treatment. The high first-day antisecretory efficacy of rabeprazole suggests a possible clinical benefit in situations that require a rapid treatment effect, such as an on-demand approach to the long-term management of gastro-oesophageal reflux disease in patients without reflux oesophagitis.