Pharmacodynamic effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg in patients with GERD and nocturnal heartburn

Authors


Dr S. Warrington, Hammersmith Medicines Research Ltd, Central Middlesex Hospital, Acton Lane, London NW10 7NS, UK.
E-mail: swarrington@hmrlondon.com

Abstract

Summary

Background

Rabeprazole and pantoprazole are both used for symptomatic treatment of gastro-oesophageal reflux disease (GERD). Speed and duration of acid suppression and intensity of effect after a single dose may be important pharmacodynamic properties in clinical use.

Aim

To compare antisecretory effects of single doses of rabeprazole and pantoprazole in patients with GERD and a history of nocturnal heartburn.

Methods

An open-label, randomized, two-way crossover, clinical pharmacology study was conducted. Twenty-nine Helicobacter pylori-negative GERD patients (17 men, mean age 44 years), with a history of nocturnal heartburn (mean frequency 4.7 episodes/week), received a single dose of rabeprazole 20 mg or pantoprazole 40 mg, with a 14-day ‘washout’. Intragastric pH was recorded continuously from 24 h before to 24 h after dosing.

Results

Mean area under the intragastric pH–time curve (AUC) was significantly higher after dosing with rabeprazole 20 mg than with pantoprazole 40 mg in all time intervals analysed, including night (P ≤ 0.02). Mean percentage time with pH > 3 and >4 was significantly greater after rabeprazole than pantoprazole in all time intervals (P ≤ 0.004).

Conclusion

In GERD patients with nocturnal heartburn, a single oral dose of rabeprazole 20 mg increased intragastric pH more than pantoprazole 40 mg did throughout the 24 h after dosing.

Introduction

Proton pump inhibitors (PPIs) are now considered to be the first-line treatment for gastro-oesophageal reflux disease (GERD). Treatment efficacy is strongly correlated with the degree and duration of acid suppression over 24 h.1,2 GERD patients who experience nocturnal symptoms may experience profound impairment of physical health, daytime function and emotional well-being, as demonstrated by measures of mental and physical well-being, pain and oesophageal erosion.3 Suppression of nocturnal acidity may be particularly important for symptom relief in such patients.

There are pharmacological differences among the PPIs after a single dose that may have implications for their clinical efficacy. For example, although all PPIs are strong inhibitors of gastric acid at steady state, rabeprazole may suppress acid output more potently after a single dose.4,5 Such pharmacological differences may also have implications for the control of nocturnal acidity.

Both pantoprazole and rabeprazole are used to treat patients with night-time reflux symptoms. Some authors have suggested that, as pantoprazole has a longer half-life than many other PPIs, it might be more effective at relieving nocturnal symptoms.3

Our study was designed to compare the antisecretory effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg in Helicobacter pylori-negative subjects who had a clinical diagnosis of GERD and a history of nocturnal heartburn. Twenty milligrams of rabeprazole and 40 mg of pantoprazole are the recommended daily doses of each drug for oesophagitis healing and symptom relief. Although there are numerous studies of the effect of PPIs on intragastric pH at steady state, there are few published reports of the pharmacodynamic effects on the first day of therapy.

Materials and methods

Subjects

Subjects were H. pylori-negative men or women aged 18–70 years, with a clinical diagnosis of GERD and a history of nocturnal heartburn (≥1 episode/week). Subjects were interviewed regarding the frequency of their symptoms. Endoscopy was not required as an entry criterion. Subjects were deemed otherwise healthy on the basis of medical history, medical examination, 12-lead ECG and laboratory safety tests. They had a body mass index of 18.0–30.9 kg/m2 and were either nonsmokers or smoked ≤5 cigarettes/day. All were negative for H. pylori by serology and 13C-urea breath test (Helicobacter diagnostic test kit; Kestrel Healthcare Ltd, Basingstoke, UK). They were not allowed to take prescription medicines during the 28 days before the start of the study, but an H2-blocker or PPI was allowed up to 14 days before the start of the study. Oral contraceptives were allowed in women. Over-the-counter medicines were not allowed within 7 days before the start of the study (with the exception of paracetamol), but antacid preparations were allowed up to 3 days before the start of the study.

Ethics

The study proposal was reviewed and approved by the Brent Medical Ethics Committee. All subjects gave written informed consent.

Study design

This study was an open-label, randomized, two-way crossover design. Subjects were resident at the study unit for two 3-day study periods separated by a washout period of at least 14 days. After an overnight fast, subjects were given a single dose of either rabeprazole 20 mg or pantoprazole 40 mg, with 100 mL of water. The order of treatment with rabeprazole or pantoprazole was randomized using an sas program (sas for Windows, version 6.12; SAS Institute, Cary, NC, USA). Intragastric pH was measured from 24 h before dosing (day 0) until 24 h after dosing. Subjects had standard meals and drinks at 1, 4 and 10 h, and went to bed (became supine) at around 14 h, after dosing on day 1, and at the corresponding times on day 0. Alcoholic drinks, caffeinated beverages, smoking, grapefruit and its juice, Seville orange and its juice, and strenuous exercise were not allowed during the interval from 48 h before day 0 until the end of each study period. On day 2, 24 h after the dose of study medication, the intragastric pH measurements were stopped, the nasogastric electrode was removed and patients were discharged after a brief physical examination, if all was well. They returned 5–10 days after the last dose of study drug for a follow-up medical examination.

Adverse events were recorded throughout the study. Subjects were questioned about adverse events at regular intervals during their stay at the study unit, and at follow-up.

Measurement of intragastric pH

Intragastric pH was recorded continuously on days 0 and 1. On day 0, after anaesthetizing the subject's nostril with 1% lidocaine hydrochloride spray, we inserted a disposable antimony internal reference pH electrode with surface markings of 1 cm (Zinetics Medical, Salt Lake City, UT, USA). pH was monitored during passage of the electrode down the oesophagus, through the gastro-oesophageal sphincter and into the stomach. We confirmed entry of the electrode into the stomach by a sharp fall in pH, usually to less than 3.2. Next, the electrode was withdrawn slowly to about 40 cm; a sharp rise in pH identified the point at which the electrode crossed the sphincter. We then advanced the electrode slowly to a final position 8–10 cm (depending on the subject's height) beyond the point at which the pH fell below 3. Intragastric pH was recorded every 6 s using a Flexilog 2020 96-h recorder (Oakfield Instruments, Oxford, UK), which had been precalibrated using buffers of pH 1.1 and 6.7, before passage of the electrode. The recorded data were uploaded to a computer using Flexisoft II software (Oakfield Instruments).

Statistical analysis

The primary efficacy variable was the area under the intragastric pH–time curve during the period from dosing on day 1 until 24 h afterwards (AUC0−−24). The primary null hypothesis was that there is no difference between rabeprazole and pantoprazole in intragastric pH AUC0−24 on day 1.

The primary analysis of the pharmacodynamic data was performed on the per-protocol population, which included all randomized subjects who received each study drug and had no appreciable loss of pH data, and excluded any with major protocol violations. The area under the intragastric pH vs. time curve (AUC) was calculated over the intervals 0–5, 5–11, 11–14, 14–24 and 0–24 h on days 0 and 1, using a linear trapezoidal method. Percentage of time when intragastric pH was >3 and >4 was calculated over the intervals 0–14, 14–24 and 0–24 h.

The null hypothesis was rejected if the two-sided P-value was ≤0.05. Data were analysed using sas for Windows, version 6.12. To test for differences between treatments in intragastric pH, a linear mixed-effect analysis of intragastric pH AUC and percentage of time with pH > 3 and >4 was performed. All models contained fixed effects for sequence, period and treatment, and random effects for subject nested within sequence. The response variable was AUC or percentage time with pH > 3 or >4 on day 1; the day 0 value was included in the model as a covariate. Day 1 AUCs were log-transformed to conform to a normal distribution, except for AUC11−14, which did not require transformation. Day 1 percentage time pH > 3 and >4 was arcsin-transformed. Statistical inference was based on the transformed variables.

The study was powered to test the hypothesis of no difference in AUC0−24 between rabeprazole and pantoprazole. Based on variability data obtained from a similar study in healthy volunteers,5 a within-subject standard deviation of intragastric pH AUC0−24 of about 40 000 pH units/s was assumed. It was thus estimated that 30 evaluable patients would have 90% power to detect a difference of 34 588 pH units/s in AUC0−24 between rabeprazole and pantoprazole, at a 5% significance level. If within-subject variability in intragastric pH AUC0−24 was as high as 47 000 pH units/s, then 30 evaluable patients would give ∼80% power to detect the same difference.

Results

Subjects

Thirty-one subjects entered the study. One man took an H2-blocker 5 days before dosing, and one man had to repeat period 1 because of a failure of the pH recorder; both subjects were excluded from the per-protocol analysis.

Twenty-nine subjects – 17 (59%) men and 12 (41%) women – completed the study according to the protocol and had pH data that were >95% complete. Their mean age was 44 years (range: 26–65 years), weight 78.4 kg (53.9–97.5 kg), height 171 cm (147–192 cm) and body mass index 26.8 kg/m2 (19.9–30.9). Twenty-two (76%) subjects were nonsmokers and seven (24%) smokers; mean daily cigarette consumption in the smoker group was 3/day. Before entering the study, subjects had a mean occurrence of nocturnal heartburn of 4.7 episodes/week (range 1.5–7).

Intragastric pH

Plots of median intragastric pH over 24 h on days 0 and 1 are in Figure 1; meal times are indicated. Mean and 95% confidence intervals (CI) of the pharmacodynamic variables are in Tables 1 and 2; statistically significant differences are indicated.

Figure 1.

 Median intragastric pH over 24 h at baseline on day 0 (top); after treatment with a single dose of rabeprazole 20 mg or pantoprazole 40 mg at 0 h on day 1 (bottom). B, breakfast; L, lunch; D, dinner; S, supine (bedtime).

Table 1.   Mean (95% CI) intragastric pH AUC at baseline (day 0) and after a single dose of rabeprazole 20 mg or pantoprazole 40 mg (n = 29)
DayInterval (h)Mean (95% CI) intragastric pH AUCP-value*
Rabeprazole 20 mgPantoprazole 40 mg
  1. P-value for difference between treatments, from linear mixed-effect analysis with day 0 value in model as a covariate.

00–540 675 (36 230–45 120)41 707 (36 626–46 787) 
5–1143 477 (37 754–49 200)42 852 (36 849–48 855) 
11–1425 540 (22 093–28 988)23 332 (20 372–26 292) 
14–2471 156 (60 523–81 790)58 398 (52 393–64 402) 
0–24180 849 (162 856–198 842)166 289 (151 342–181 237) 
10–557 327 (51 868–62 786)51 468 (46 458–56 479)0.016
5–1194 894 (83 874–105 914)72 604 (63 882–81 327)0.0005
11–1452 283 (46 537–58 030)40 970 (36 567–45 374)0.0005
14–24115 096 (100 089–130 103)94 863 (82 887–106 839)0.003
0–24319 692 (291 431–347 952)259 921 (234 674–285 168)<0.0001
Table 2.   Mean (95% confidence interval) percentage of time with intragastric pH > 3 and >4 at baseline (day 0) and after single dose of rabeprazole 20 mg or pantoprazole 40 mg (n = 29)
DayInterval (h)pH > 3P-value*
RabeprazolePantoprazole
  1. P-value for difference between treatments, from linear mixed-effect analysis with day 0 value in model as a covariate.

00–1421.8 (15.1–28.4)21.0 (14.3–27.6) 
14–2412.1 (5.8–18.4)5.2 (2.2–8.2) 
0–2417.7 (12.6–22.9)14.4 (10.3–18.6) 
10–1463.9 (56.3–71.5)49.8 (41.6–57.9)0.001
14–2439.5 (29.0–50.0)25.4 (16.8–34.0)0.0009
0–2453.8 (46.5–61.1)39.6 (31.8–47.4)0.0001
  pH > 4 
00–1412.1 (6.2–17.9)12.5 (6.8–18.1) 
14–248.7 (3.4–14.0)3.2 (1.1–5.4) 
0–2410.6 (6.3–15.0)8.6 (5.3–11.9) 
10–1452.6 (43.8–61.4)36.7 (27.8–45.6)0.0003
14–2428.1 (18.8–37.5)17.3 (10.2–24.5)0.004
0–2442.4 (34.7–50.2)28.6 (21.1–36.1)<0.0001

The effects of study period and treatment sequence (the order in which the subject had rabeprazole and pantoprazole) on intragastric pH AUC and the percentage of time with pH > 3 and >4 were not statistically significant in any of the analyses. The lack of a statistically significant sequence effect indicates that the carryover of treatment effects from the first period to the second did not exist or was not detectable.

On day 1, mean intragastric pH AUC0−24 was significantly higher after rabeprazole 20 mg than after pantoprazole 40 mg: 319 692 vs. 259 921 pH units/s, respectively (P < 0.0001). Mean pH AUC was significantly higher after rabeprazole than pantoprazole in all time intervals studied: 0–5, 5–11, 11–14 and 14–24 h. The difference was particularly marked 5–24 h after dosing (Figure 1).

Mean percentage time pH > 3 and >4 on day 1 was significantly higher after rabeprazole than pantoprazole during the 24 h after dosing and in all time intervals (Table 2; P ≤ 0.004).

Individual subjects’ percentage time pH > 4 are shown in Figures 2 and 3. During the 24 h after dosing, pH was maintained >4 for at least 12 h in nine subjects (31.0%) after rabeprazole and in three subjects (10.3%) after pantoprazole.

Figure 2.

 Individual subjects’ data for percentage time pH > 4 over 24 h at baseline on day 0 (top); after treatment with a single dose of rabeprazole or pantoprazole on day 1 (bottom).

Figure 3.

 Individual subjects’ data for percentage time pH > 4 during night (14–24 h) at baseline on day 0 (top); after treatment with a single dose of rabeprazole or pantoprazole on day 1 (bottom) .

Safety

Single oral doses of rabeprazole 20 mg and pantoprazole 40 mg were safe and well tolerated in GERD patients with nocturnal heartburn, as shown by vital signs, physical examination, 12-lead ECG, laboratory safety tests and adverse events.

Consistent with clinical experience, adverse events after both rabeprazole and pantoprazole were headache (41.9% of subjects; 27.6% of events), and gastrointestinal disturbances, including indigestion, nausea and abdominal discomfort (25.8% of subjects; 13.1% of events). Most of these events were mild. There was no clinically relevant difference between rabeprazole 20 mg or pantoprazole 40 mg with respect to the nature or intensity of the adverse events.

Discussion

Overall, and during each time interval (including the overnight hours), a single oral dose of rabeprazole 20 mg increased intragastric pH significantly more than did pantoprazole 40 mg in GERD patients with a history of nocturnal heartburn. In addition, mean percentage time pH > 4 was significantly higher after rabeprazole than pantoprazole during the 24 h after dosing and in all time intervals analysed.

Our results are consistent with those of a previous study in healthy H. pylori-negative volunteers, which showed that a single dose of rabeprazole 20 mg maintained pH > 4 for a greater proportion of the 24 h after dosing than did pantoprazole 40 mg, lansoprazole 30 mg or omeprazole 20 mg.4 Furthermore, the authors showed that night-time pH (14–22 h after dosing) was higher after a single dose of rabepraozole 20 mg than pantoprazole 40 mg or omeprazole 20 mg.4 Our results are also compatible with those of a study in patients with gastric or duodenal ulcer, in which single doses of rabeprazole 10 mg yielded a significantly greater acid suppressant effect than did pantoprazole 40 mg or omeprazole 20 mg, as judged by nocturnal acid breakthrough and nocturnal alkaline amplitude.6

As the acid suppressant effect of rabeprazole 20 mg significantly exceeded that of pantoprazole 40 mg, it is clear that in our study population, oral rabeprazole was pharmacologically more than twice as potent as oral pantoprazole on an mg-per-mg basis. However, it should be noted that the results reported here apply only to single doses of the drugs. Only one study has directly compared the pharmacodynamic effects of repeated doses of rabeprazole and pantoprazole, as part of a crossover study comparing five PPIs in GERD patients.7 The results were compatible with our findings in that the effects on intragastric pH of 5 days’ treatment with rabeprazole 20 mg were numerically greater than those of pantoprazole 40 mg. However, the authors did not present the statistical significance of the differences.

One possible limitation of our study is its open-label design. However, the endpoint, intragastric pH, is an objective measurement; therefore, we do not believe that the open design is a serious limitation.

Our results are of potential clinical relevance to the use of rabeprazole at the start of continuous therapy in symptomatic patients with GERD, when, ideally, the first dose should have a profound effect. Our findings may also be relevant to the intermittent or on-demand use of rabeprazole in uncomplicated GERD. Such use requires a PPI with a substantial effect on intragastric pH that is sustained over the 24 h after a single dose. Studies of on-demand use of rabeprazole suggest that it controls symptoms effectively.8,9 National guidelines in the UK now recommend on-demand therapy for GERD, not only because it promotes patients’ involvement in the management of their disease, but also because it should be less expensive, as patients take an average of 0.4 tablets/day.10

Relief of nocturnal reflux requires a medication with an acid suppressant effect that is sustained into the overnight hours. In our study, a single dose of rabeprazole increased intragastric pH to a significantly greater extent than did pantoprazole during all time intervals up to 24 h after dosing. The difference between treatments was most marked in the 5- to 24-h period. Although pantoprazole has a slightly longer half-life than rabeprazole (1.2 h vs. 1.0 h), we found the effect of rabeprazole on intragastric pH to be more sustained, as demonstrated by the significantly greater percentage of time with pH > 3 and >4 after rabeprazole 20 mg than after pantoprazole 40 mg for all time intervals. If GERD patients were to take a single dose of these drugs during the first half of the day, rabeprazole might be expected to be the more effective treatment in preventing nocturnal heartburn. However, clinical trials would be needed to test that expectation.

In summary, in patients with GERD and nocturnal heartburn, we found that mean area under the intragastric pH–time curve (AUC) and the mean percentage time with pH > 3 and >4 were significantly higher after a single dose of rabeprazole 20 mg than after pantoprazole 40 mg in all time intervals analysed, including night time. These doses are the ones currently recommended for use in GERD. Rabeprazole was pharmacologically more potent than pantoprazole, by the oral route.

Acknowledgement

Authors' declaration of personal interests: K. Lomax is an employee of Eisai Inc. B. Delemos is an employee of Pricara. A. Morocutti is an employee of Eisai Ltd.

Declaration of funding interests: the study was funded in full by Eisai Inc., USA and Pricara, Unit of Ortho-McNeil Inc.

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