Pharmacodynamic Effects of Single Doses of Rabeprazole 20 Mg And

Alimentary Pharmacology & Therapeutics

Pharmacodynamic effects of single doses of rabeprazole 20 mg and pantoprazole 40 mg in patients with GERD and nocturnal heartburn S.WARRINGTON*,K.BAISLEY*,D.LEE*,K.LOMAX ,B.DELEMOSà,M.BOYCE*&A.MOROCUTTI§

*Hammersmith Medicines Research SUMMARY Ltd, Central Middlesex Hospital, London, UK; Medical Affairs, Eisai Background Inc., Teaneck, NJ, USA; àPriCara, Unit Rabeprazole and pantoprazole are both used for symptomatic treatment of Ortho-McNeil Inc., Raritan, NJ, USA; §Medical Affairs, Eisai Ltd, of gastro-oesophageal reﬂux disease (GERD). Speed and duration of acid London, UK suppression and intensity of effect after a single dose may be important pharmacodynamic properties in clinical use. Correspondence to: Dr S. Warrington, Hammersmith Aim Medicines Research Ltd, Central Middlesex Hospital, Acton Lane, To compare antisecretory effects of single doses of rabeprazole and pan- London NW10 7NS, UK. toprazole in patients with GERD and a history of nocturnal heartburn. E-mail: [email protected] Methods An open-label, randomized, two-way crossover, clinical pharmacology Publication data Submitted 30 August 2006 study was conducted. Twenty-nine Helicobacter pylori-negative GERD First decision 5 September 2006 patients (17 men, mean age 44 years), with a history of nocturnal heart- Resubmitted 18 October 2006 burn (mean frequency 4.7 episodes/week), received a single dose of Accepted 6 November 2006 rabeprazole 20 mg or pantoprazole 40 mg, with a 14-day ‘washout’. In- tragastric 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.

Aliment Pharmacol Ther 25, 511–517

ª 2007 The Authors 511 Journal compilation ª 2007 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2006.03196.x 512 S. WARRINGTON et al.

mass index of 18.0–30.9 kg/m2 and were either non- INTRODUCTION smokers or smoked £5 cigarettes/day. All were negat- Proton pump inhibitors (PPIs) are now considered to be ive for H. pylori by serology and 13C-urea breath test the first-line treatment for gastro-oesophageal reflux (Helicobacter diagnostic test kit; Kestrel Healthcare Ltd, disease (GERD). Treatment efficacy is strongly correla- Basingstoke, UK). They were not allowed to take pre- ted with the degree and duration of acid suppression scription medicines during the 28 days before the start 1,2 over 24 h. GERD patients who experience nocturnal of the study, but an H2-blocker or PPI was allowed up symptoms may experience profound impairment of to 14 days before the start of the study. Oral contra- physical health, daytime function and emotional well- ceptives were allowed in women. Over-the-counter being, as demonstrated by measures of mental and medicines were not allowed within 7 days before the physical well-being, pain and oesophageal erosion.3 start of the study (with the exception of paracetamol), Suppression of nocturnal acidity may be particularly but antacid preparations were allowed up to 3 days important for symptom relief in such patients. before the start of the study. There are pharmacological differences among the PPIs after a single dose that may have implications for Ethics their clinical efficacy. For example, although all PPIs are strong inhibitors of gastric acid at steady state, The study proposal was reviewed and approved by the rabeprazole may suppress acid output more potently Brent Medical Ethics Committee. All subjects gave after a single dose.4,5 Such pharmacological differ- written informed consent. ences may also have implications for the control of nocturnal acidity. Study design Both pantoprazole and rabeprazole are used to treat patients with night-time reflux symptoms. Some This study was an open-label, randomized, two-way authors have suggested that, as pantoprazole has a crossover design. Subjects were resident at the study longer half-life than many other PPIs, it might be unit for two 3-day study periods separated by a wash- more effective at relieving nocturnal symptoms.3 out period of at least 14 days. After an overnight fast, Our study was designed to compare the antisecretory subjects were given a single dose of either rabeprazole effects of single doses of rabeprazole 20 mg and pan- 20 mg or pantoprazole 40 mg, with 100 mL of water. toprazole 40 mg in Helicobacter pylori-negative sub- The order of treatment with rabeprazole or pantopraz- jects who had a clinical diagnosis of GERD and a ole was randomized using an SAS program (SAS for history of nocturnal heartburn. Twenty milligrams of Windows, version 6.12; SAS Institute, Cary, NC, USA). rabeprazole and 40 mg of pantoprazole are the recom- Intragastric pH was measured from 24 h before dosing mended daily doses of each drug for oesophagitis heal- (day 0) until 24 h after dosing. Subjects had standard ing and symptom relief. Although there are numerous meals and drinks at 1, 4 and 10 h, and went to bed studies of the effect of PPIs on intragastric pH at steady (became supine) at around 14 h, after dosing on day 1, state, there are few published reports of the pharmaco- and at the corresponding times on day 0. Alcoholic dynamic effects on the first day of therapy. drinks, caffeinated beverages, smoking, grapefruit and its juice, Seville orange and its juice, and strenuous exercise were not allowed during the interval from MATERIALS AND METHODS 48 h before day 0 until the end of each study period. On day 2, 24 h after the dose of study medication, the Subjects intragastric pH measurements were stopped, the naso- Subjects were H. pylori-negative men or women aged gastric electrode was removed and patients were dis- 18–70 years, with a clinical diagnosis of GERD and a charged after a brief physical examination, if all was history of nocturnal heartburn (‡1 episode/week). Sub- well. They returned 5–10 days after the last dose of jects were interviewed regarding the frequency of their study drug for a follow-up medical examination. symptoms. Endoscopy was not required as an entry Adverse events were recorded throughout the study. criterion. Subjects were deemed otherwise healthy on Subjects were questioned about adverse events at the basis of medical history, medical examination, 12- regular intervals during their stay at the study unit, lead ECG and laboratory safety tests. They had a body and at follow-up.

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contained fixed effects for sequence, period and treat- Measurement of intragastric pH ment, and random effects for subject nested within Intragastric pH was recorded continuously on days 0 sequence. The response variable was AUC or percent- and 1. On day 0, after anaesthetizing the subject’s age time with pH > 3 or >4 on day 1; the day 0 value nostril with 1% lidocaine hydrochloride spray, we was included in the model as a covariate. Day 1 AUCs inserted a disposable antimony internal reference pH were log-transformed to conform to a normal distribu- electrode with surface markings of 1 cm (Zinetics tion, except for AUC11)14, which did not require trans- Medical, Salt Lake City, UT, USA). pH was monitored formation. Day 1 percentage time pH > 3 and >4 was during passage of the electrode down the oesophagus, arcsin-transformed. Statistical inference was based on through the gastro-oesophageal sphincter and into the transformed variables. the stomach. We confirmed entry of the electrode The study was powered to test the hypothesis of no into the stomach by a sharp fall in pH, usually to difference in AUC0)24 between rabeprazole and pan- less than 3.2. Next, the electrode was withdrawn toprazole. Based on variability data obtained from a slowly to about 40 cm; a sharp rise in pH identified similar study in healthy volunteers,5 a within-subject the point at which the electrode crossed the sphinc- standard deviation of intragastric pH AUC0)24 of about ter. We then advanced the electrode slowly to a final 40 000 pH units/s was assumed. It was thus estimated position 8–10 cm (depending on the subject’s height) that 30 evaluable patients would have 90% power to beyond the point at which the pH fell below 3. Intra- detect a difference of 34 588 pH units/s in AUC0)24 gastric pH was recorded every 6 s using a Flexilog between rabeprazole and pantoprazole, at a 5% signi- 2020 96-h recorder (Oakfield Instruments, Oxford, ficance level. If within-subject variability in intragas-

UK), which had been precalibrated using buffers of tric pH AUC0)24 was as high as 47 000 pH units/s, pH 1.1 and 6.7, before passage of the electrode. The then 30 evaluable patients would give 80% power to recorded data were uploaded to a computer using detect the same difference. Flexisoft II software (Oakﬁeld Instruments). RESULTS Statistical analysis Subjects The primary efﬁcacy variable was the area under the intragastric pH–time curve during the period from Thirty-one subjects entered the study. One man took dosing on day 1 until 24 h afterwards (AUC0))24). The an H2-blocker 5 days before dosing, and one man had primary null hypothesis was that there is no difference to repeat period 1 because of a failure of the pH recor- between rabeprazole and pantoprazole in intragastric der; both subjects were excluded from the per-protocol pH AUC0)24 on day 1. analysis. The primary analysis of the pharmacodynamic data Twenty-nine subjects – 17 (59%) men and 12 was performed on the per-protocol population, which (41%) women – completed the study according to the included all randomized subjects who received each protocol and had pH data that were >95% complete. study drug and had no appreciable loss of pH data, Their mean age was 44 years (range: 26–65 years), and excluded any with major protocol violations. The weight 78.4 kg (53.9–97.5 kg), height 171 cm (147– area under the intragastric pH vs. time curve (AUC) 192 cm) and body mass index 26.8 kg/m2 (19.9– was calculated over the intervals 0–5, 5–11, 11–14, 30.9). Twenty-two (76%) subjects were nonsmokers 14–24 and 0–24 h on days 0 and 1, using a linear tra- and seven (24%) smokers; mean daily cigarette con- pezoidal method. Percentage of time when intragastric sumption in the smoker group was 3/day. Before pH was >3 and >4 was calculated over the intervals entering the study, subjects had a mean occurrence 0–14, 14–24 and 0–24 h. of nocturnal heartburn of 4.7 episodes/week (range The null hypothesis was rejected if the two-sided 1.5–7). P-value was £0.05. Data were analysed using SAS for Windows, version 6.12. To test for differences between Intragastric pH treatments in intragastric pH, a linear mixed-effect analysis of intragastric pH AUC and percentage of Plots of median intragastric pH over 24 h on days 0 time with pH > 3 and >4 was performed. All models and 1 are in Figure 1; meal times are indicated. Mean

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7.0

Day 0 rabeprazole 6.0 Day 0 pantoprazole B L D 5.0 S

4.0

3.0 Median pH

2.0

1.0

0.0 –1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Time relative to dosing (h)

7.0

L D Day 1 rabeprazole 6.0 Day 1 pantoprazole B S

5.0

4.0

3.0

Median pH Figure 1. Median intragastric pH over 24 h at baseline on 2.0 day 0 (top); after treatment with a single dose of rabeprazole 20 mg or pantoprazole 1.0 40 mg at 0 h on day 1 (bottom). B, breakfast; L, 0.0 lunch; D, dinner; S, supine –1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 (bedtime). Time relative to dosing (h)

and 95% confidence intervals (CI) of the pharmacody- respectively (P < 0.0001). Mean pH AUC was signifi- namic variables are in Tables 1 and 2; statistically sig- cantly higher after rabeprazole than pantoprazole in nificant differences are indicated. all time intervals studied: 0–5, 5–11, 11–14 and 14– The effects of study period and treatment sequence 24 h. The difference was particularly marked 5–24 h (the order in which the subject had rabeprazole and after dosing (Figure 1). pantoprazole) on intragastric pH AUC and the percent- Mean percentage time pH > 3 and >4 on day 1 was age of time with pH > 3 and >4 were not statistically significantly higher after rabeprazole than pantop- significant in any of the analyses. The lack of a statis- razole during the 24 h after dosing and in all time tically significant sequence effect indicates that the intervals (Table 2; P £ 0.004). carryover of treatment effects from the first period to Individual subjects’ percentage time pH > 4 are the second did not exist or was not detectable. shown in Figures 2 and 3. During the 24 h after dos-

On day 1, mean intragastric pH AUC0)24 was signiﬁ- ing, pH was maintained >4 for at least 12 h in nine cantly higher after rabeprazole 20 mg than after pan- subjects (31.0%) after rabeprazole and in three subjects toprazole 40 mg: 319 692 vs. 259 921 pH units/s, (10.3%) after pantoprazole.

ª 2007 The Authors, Aliment Pharmacol Ther 25, 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd RABEPRAZOLE VS. PANTOPRAZOLE IN GERD PATIENTS 515

Table 1. Mean (95% CI) intra- Mean (95% CI) intragastric pH AUC gastric pH AUC at baseline Interval (day 0) and after a single dose Day (h) Rabeprazole 20 mg Pantoprazole 40 mg P-value* of rabeprazole 20 mg or pantoprazole 40 mg (n 29) ¼ 0 0–5 40 675 (36 230–45 120) 41 707 (36 626–46 787) 5–11 43 477 (37 754–49 200) 42 852 (36 849–48 855) 11–14 25 540 (22 093–28 988) 23 332 (20 372–26 292) 14–24 71 156 (60 523–81 790) 58 398 (52 393–64 402) 0–24 180 849 (162 856–198 842) 166 289 (151 342–181 237) 1 0–5 57 327 (51 868–62 786) 51 468 (46 458–56 479) 0.016 5–11 94 894 (83 874–105 914) 72 604 (63 882–81 327) 0.0005 11–14 52 283 (46 537–58 030) 40 970 (36 567–45 374) 0.0005 14–24 115 096 (100 089–130 103) 94 863 (82 887–106 839) 0.003 0–24 319 692 (291 431–347 952) 259 921 (234 674–285 168) <0.0001

* P-value for difference between treatments, from linear mixed-effect analysis with day 0 value in model as a covariate.

Table 2. Mean (95% conﬁdence interval) percentage of 100 Day 0 time with intragastric pH > 3 and >4 at baseline (day 0) 90 (0–24 h) and after single dose of rabeprazole 20 mg or pantopraz- 80 ole 40 mg (n ¼ 29) 70

pH > 3 60

Interval 50 Day (h) Rabeprazole Pantoprazole P-value* 40

0 0–14 21.8 (15.1–28.4) 21.0 (14.3–27.6) Percent time pH >4 30 14–24 12.1 (5.8–18.4) 5.2 (2.2–8.2) 20 0–24 17.7 (12.6–22.9) 14.4 (10.3–18.6) 10 1 0–14 63.9 (56.3–71.5) 49.8 (41.6–57.9) 0.001 0 14–24 39.5 (29.0–50.0) 25.4 (16.8–34.0) 0.0009 Rabeprazole 20 mg Pantoprazole 40 mg 0–24 53.8 (46.5–61.1) 39.6 (31.8–47.4) 0.0001 100 pH > 4 Day 1 90 (0–24 h) 0 0–14 12.1 (6.2–17.9) 12.5 (6.8–18.1) 80 14–24 8.7 (3.4–14.0) 3.2 (1.1–5.4) 70

0–24 10.6 (6.3–15.0) 8.6 (5.3–11.9) 60 1 0–14 52.6 (43.8–61.4) 36.7 (27.8–45.6) 0.0003 14–24 28.1 (18.8–37.5) 17.3 (10.2–24.5) 0.004 50 0–24 42.4 (34.7–50.2) 28.6 (21.1–36.1) <0.0001 40

Percent time pH >4 30

* P-value for difference between treatments, from linear 20 mixed-effect analysis with day 0 value in model as a covariate. 10

0 Rabeprazole 20 mg Pantoprazole 40 mg

Safety Figure 2. Individual subjects’ data for percentage time Single oral doses of rabeprazole 20 mg and pantopraz- pH > 4 over 24 h at baseline on day 0 (top); after treat- ole 40 mg were safe and well tolerated in GERD ment with a single dose of rabeprazole or pantoprazole on day 1 (bottom). patients with nocturnal heartburn, as shown by vital

ª 2007 The Authors, Aliment Pharmacol Ther 25, 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd 516 S. WARRINGTON et al.

100 history of nocturnal heartburn. In addition, mean per- Day 0 night 90 (14–24 h) centage time pH > 4 was signiﬁcantly higher after 80 rabeprazole than pantoprazole during the 24 h after 70 dosing and in all time intervals analysed. 60 Our results are consistent with those of a previous study in healthy H. pylori-negative volunteers, which 50 showed that a single dose of rabeprazole 20 mg main- 40 tained pH > 4 for a greater proportion of the 24 h

Percent time pH >4 30 after dosing than did pantoprazole 40 mg, lansopra- 20 zole 30 mg or omeprazole 20 mg.4 Furthermore, the 10 authors showed that night-time pH (14–22 h after dos- 0 ing) was higher after a single dose of rabepraozole Rabeprazole 20 mg Pantoprazole 40 mg 20 mg than pantoprazole 40 mg or omeprazole 100 20 mg.4 Our results are also compatible with those of Day 1 night 90 (14–24 h) a study in patients with gastric or duodenal ulcer, in 80 which single doses of rabeprazole 10 mg yielded a sig- 70 niﬁcantly greater acid suppressant effect than did pan- 60 toprazole 40 mg or omeprazole 20 mg, as judged by nocturnal acid breakthrough and nocturnal alkaline 50 amplitude.6 40 As the acid suppressant effect of rabeprazole 20 mg

Percent time pH >4 30 significantly exceeded that of pantoprazole 40 mg, it 20 is clear that in our study population, oral rabeprazole 10 was pharmacologically more than twice as potent as 0 Rabeprazole 20 mg Pantoprazole 40 mg 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 Figure 3. Individual subjects’ data for percentage time pH > 4 during night (14–24 h) at baseline on day 0 (top); directly compared the pharmacodynamic effects of after treatment with a single dose of rabeprazole or pan- repeated doses of rabeprazole and pantoprazole, as toprazole on day 1 (bottom) . 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’ signs, physical examination, 12-lead ECG, laboratory treatment with rabeprazole 20 mg were numerically safety tests and adverse events. greater than those of pantoprazole 40 mg. However, Consistent with clinical experience, adverse events the authors did not present the statistical significance after both rabeprazole and pantoprazole were head- of the differences. ache (41.9% of subjects; 27.6% of events), and gastro- One possible limitation of our study is its open-label intestinal disturbances, including indigestion, nausea design. However, the endpoint, intragastric pH, is an and abdominal discomfort (25.8% of subjects; 13.1% objective measurement; therefore, we do not believe of events). Most of these events were mild. There was that the open design is a serious limitation. no clinically relevant difference between rabeprazole Our results are of potential clinical relevance to the 20 mg or pantoprazole 40 mg with respect to the nat- use of rabeprazole at the start of continuous therapy ure or intensity of the adverse events. 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 DISCUSSION use of rabeprazole in uncomplicated GERD. Such use Overall, and during each time interval (including the requires a PPI with a substantial effect on intragastric overnight hours), a single oral dose of rabeprazole pH that is sustained over the 24 h after a single dose. 20 mg increased intragastric pH significantly more Studies of on-demand use of rabeprazole suggest that than did pantoprazole 40 mg in GERD patients with a it controls symptoms effectively.8,9 National guidelines

ª 2007 The Authors, Aliment Pharmacol Ther 25, 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd RABEPRAZOLE VS. PANTOPRAZOLE IN GERD PATIENTS 517 in the UK now recommend on-demand therapy for treatment in preventing nocturnal heartburn. However, GERD, not only because it promotes patients’ involve- clinical trials would be needed to test that expectation. ment in the management of their disease, but also In summary, in patients with GERD and nocturnal because it should be less expensive, as patients take heartburn, we found that mean area under the intra- an average of 0.4 tablets/day.10 gastric pH–time curve (AUC) and the mean percentage Relief of nocturnal reflux requires a medication with time with pH > 3 and >4 were significantly higher an acid suppressant effect that is sustained into the after a single dose of rabeprazole 20 mg than after overnight hours. In our study, a single dose of rabep- pantoprazole 40 mg in all time intervals analysed, razole increased intragastric pH to a significantly including night time. These doses are the ones cur- greater extent than did pantoprazole during all time rently recommended for use in GERD. Rabeprazole intervals up to 24 h after dosing. The difference was pharmacologically more potent than pantoprazole, between treatments was most marked in the 5- to 24- by the oral route. h period. Although pantoprazole has a slightly longer half-life than rabeprazole (1.2 h vs. 1.0 h), we found ACKNOWLEDGEMENT the effect of rabeprazole on intragastric pH to be more sustained, as demonstrated by the significantly greater Authors’ declaration of personal interests: K. Lomax is percentage of time with pH > 3 and >4 after rabepraz- an employee of Eisai Inc. B. Delemos is an employee ole 20 mg than after pantoprazole 40 mg for all time of Pricara. A. Morocutti is an employee of Eisai Ltd. intervals. If GERD patients were to take a single dose Declaration of funding interests: the study was of these drugs during the first half of the day, rabep- funded in full by Eisai Inc., USA and Pricara, Unit of razole might be expected to be the more effective Ortho-McNeil Inc.

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