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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 Ltd, Central Middlesex Hospital, London, UK;  Medical Affairs, Eisai Inc., Teaneck, NJ, USA; àPriCara, Unit of Ortho-McNeil Inc., Raritan, NJ, USA; §Medical Affairs, Eisai Ltd, London, UK Correspondence to: Dr S. Warrington, Hammersmith Medicines Research Ltd, Central Middlesex Hospital, Acton Lane, London NW10 7NS, UK. E-mail: swarrington@hmrlondon.com

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.
Aliment Pharmacol Ther 25, 511–517

Publication data Submitted 30 August 2006 First decision 5 September 2006 Resubmitted 18 October 2006 Accepted 6 November 2006

ª 2007 The Authors Journal compilation ª 2007 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2006.03196.x

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SAS Institute.4. the nasogastric electrode was removed and patients were discharged after a brief physical examination. Adverse events were recorded throughout the study. After an overnight fast. 24 h after the dose of study medication. NC. Subjects were questioned about adverse events at regular intervals during their stay at the study unit. Over-the-counter medicines were not allowed within 7 days before the start of the study (with the exception of paracetamol). On day 2. smoking. there are few published reports of the pharmacodynamic effects on the first day of therapy. 12lead ECG and laboratory safety tests. Some authors have suggested that. Kestrel Healthcare Ltd. it might be more effective at relieving nocturnal symptoms. UK). W A R R I N G T O N et al. INTRODUCTION Proton pump inhibitors (PPIs) are now considered to be the first-line treatment for gastro-oesophageal reflux disease (GERD).3 Suppression of nocturnal acidity may be particularly important for symptom relief in such patients. pylori by serology and 13C-urea breath test (Helicobacter diagnostic test kit. Oral contraceptives were allowed in women. medical examination. after dosing on day 1. ª 2007 The Authors. two-way crossover design. Subjects were deemed otherwise healthy on the basis of medical history.2 GERD patients who experience nocturnal symptoms may experience profound impairment of physical health. but an H2-blocker or PPI was allowed up to 14 days before the start of the study. Twenty milligrams of rabeprazole and 40 mg of pantoprazole are the recommended daily doses of each drug for oesophagitis healing and symptom relief. Subjects were resident at the study unit for two 3-day study periods separated by a washout period of at least 14 days. and at follow-up. Treatment efficacy is strongly correlated with the degree and duration of acid suppression over 24 h. USA). The order of treatment with rabeprazole or pantoprazole was randomized using an SAS program (SAS for Windows. Basingstoke.0–30.1. Seville orange and its juice. daytime function and emotional wellbeing.12. All subjects gave written informed consent. grapefruit and its juice. Endoscopy was not required as an entry criterion. if all was well. pain and oesophageal erosion.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. Intragastric pH was measured from 24 h before dosing (day 0) until 24 h after dosing. They returned 5–10 days after the last dose of study drug for a follow-up medical examination. All were negative for H. rabeprazole may suppress acid output more potently after a single dose. with a clinical diagnosis of GERD and a history of nocturnal heartburn (‡1 episode/week). Study design This study was an open-label. Ethics The study proposal was reviewed and approved by the Brent Medical Ethics Committee.9 kg/m2 and were either nonsmokers or smoked £5 cigarettes/day. subjects were given a single dose of either rabeprazole 20 mg or pantoprazole 40 mg. 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd MATERIALS AND METHODS Subjects Subjects were H. Although there are numerous studies of the effect of PPIs on intragastric pH at steady state. and at the corresponding times on day 0. Cary. and strenuous exercise were not allowed during the interval from 48 h before day 0 until the end of each study period. They were not allowed to take prescription medicines during the 28 days before the start of the study. Subjects had standard meals and drinks at 1. For example. but antacid preparations were allowed up to 3 days before the start of the study. caffeinated beverages. Subjects were interviewed regarding the frequency of their symptoms. version 6. Aliment Pharmacol Ther 25. Alcoholic drinks. Both pantoprazole and rabeprazole are used to treat patients with night-time reflux symptoms. the intragastric pH measurements were stopped. with 100 mL of water. mass index of 18. and went to bed (became supine) at around 14 h. 4 and 10 h.512 S .5 Such pharmacological differences may also have implications for the control of nocturnal acidity. although all PPIs are strong inhibitors of gastric acid at steady state. as pantoprazole has a longer half-life than many other PPIs. as demonstrated by measures of mental and physical well-being. They had a body . There are pharmacological differences among the PPIs after a single dose that may have implications for their clinical efficacy. pylori-negative men or women aged 18–70 years. randomized.

8 kg/m2 (19. through the gastro-oesophageal sphincter and into the stomach. and one man had to repeat period 1 because of a failure of the pH recorder. The recorded data were uploaded to a computer using Flexisoft II software (Oakfield Instruments). 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. 5–11. The response variable was AUC or percentage time with pH > 3 or >4 on day 1. Twenty-two (76%) subjects were nonsmokers and seven (24%) smokers. using a linear trapezoidal method. 14–24 and 0–24 h. which included all randomized subjects who received each study drug and had no appreciable loss of pH data. On day 0. before passage of the electrode. We confirmed entry of the electrode into the stomach by a sharp fall in pH. Statistical inference was based on the transformed variables. If within-subject variability in intragastric pH AUC0)24 was as high as 47 000 pH units/s. Data were analysed using SAS for Windows. 14–24 and 0–24 h on days 0 and 1. which had been precalibrated using buffers of pH 1. the electrode was withdrawn slowly to about 40 cm. P A N T O P R A Z O L E I N G E R D P A T I E N T S 513 Measurement of intragastric pH Intragastric pH was recorded continuously on days 0 and 1. mean daily cigarette consumption in the smoker group was 3/day. after anaesthetizing the subject’s nostril with 1% lidocaine hydrochloride spray. a sharp rise in pH identified the point at which the electrode crossed the sphincter. The primary analysis of the pharmacodynamic data was performed on the per-protocol population. Salt Lake City. UK). 11–14.9– 30. 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd Subjects Thirty-one subjects entered the study. version 6. All models ª 2007 The Authors. Percentage of time when intragastric pH was >3 and >4 was calculated over the intervals 0–14. height 171 cm (147– 192 cm) and body mass index 26.7 episodes/week (range 1. Oxford. except for AUC11)14. The study was powered to test the hypothesis of no difference in AUC0)24 between rabeprazole and pantoprazole. then 30 evaluable patients would give 80% power to detect the same difference.5 a within-subject standard deviation of intragastric pH AUC0)24 of about 40 000 pH units/s was assumed. Next. period and treatment. which did not require transformation. at a 5% significance level. contained fixed effects for sequence. Day 1 percentage time pH > 3 and >4 was arcsin-transformed. Before entering the study.12. and excluded any with major protocol violations. Their mean age was 44 years (range: 26–65 years). 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. we inserted a disposable antimony internal reference pH electrode with surface markings of 1 cm (Zinetics Medical. the day 0 value was included in the model as a covariate.9). and random effects for subject nested within sequence.5 kg). Intragastric pH was recorded every 6 s using a Flexilog 2020 96-h recorder (Oakfield Instruments. a linear mixed-effect analysis of intragastric pH AUC and percentage of time with pH > 3 and >4 was performed.7. usually to less than 3. meal times are indicated. RESULTS 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).R A B E P R A Z O L E V S . To test for differences between treatments in intragastric pH. The area under the intragastric pH vs. One man took an H2-blocker 5 days before dosing.05. time curve (AUC) was calculated over the intervals 0–5.5–7).9–97. UT. Intragastric pH Plots of median intragastric pH over 24 h on days 0 and 1 are in Figure 1. Based on variability data obtained from a similar study in healthy volunteers.2. Day 1 AUCs were log-transformed to conform to a normal distribution. subjects had a mean occurrence of nocturnal heartburn of 4. Mean . 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 3.4 kg (53. Aliment Pharmacol Ther 25. weight 78. USA).1 and 6. both subjects were excluded from the per-protocol analysis. pH was monitored during passage of the electrode down the oesophagus. The primary null hypothesis was that there is no difference between rabeprazole and pantoprazole in intragastric pH AUC0)24 on day 1. The null hypothesis was rejected if the two-sided P-value was £0.

0 Day 0 rabeprazole 6.3%) after pantoprazole.0 3.0 2.0001).0 L D S Median pH 4.0 0. ª 2007 The Authors. L.0 2.0 –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) Figure 1. 7. Mean pH AUC was significantly higher after rabeprazole than pantoprazole in all time intervals studied: 0–5.0 0. B. Median intragastric pH over 24 h at baseline on day 0 (top).0 L 6. On day 1. During the 24 h after dosing. Individual subjects’ percentage time pH > 4 are shown in Figures 2 and 3.0 –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. after treatment with a single dose of rabeprazole 20 mg or pantoprazole 40 mg at 0 h on day 1 (bottom). Aliment Pharmacol Ther 25. and 95% confidence intervals (CI) of the pharmacodynamic variables are in Tables 1 and 2.0 3. breakfast. supine (bedtime).0 Day 0 pantoprazole B 5. 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. 11–14 and 14– 24 h. W A R R I N G T O N et al.0%) after rabeprazole and in three subjects (10. 259 921 pH units/s. respectively (P < 0. 5–11.004). mean intragastric pH AUC0)24 was significantly higher after rabeprazole 20 mg than after pantoprazole 40 mg: 319 692 vs. pH was maintained >4 for at least 12 h in nine subjects (31. The difference was particularly marked 5–24 h after dosing (Figure 1). lunch.0 D Day 1 rabeprazole Day 1 pantoprazole B 5.0 1. 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. 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd . D. S. dinner. statistically significant differences are indicated. 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. P £ 0.0 1.0 S Median pH 4.514 S .

4) (12. 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 ¼ 29) pH > 3 Interval Day (h) Rabeprazole 0 0–14 14–24 0–24 0–14 14–24 0–24 21.R A B E P R A Z O L E V S .0009 0.5 53.2–8.6 (14.8–61.6–57.6) (2.8 12.6 52.3–15. from linear mixed-effect analysis with day 0 value in model as a covariate.7 63.3–71.3 28. Table 2.0) (31.0001 * P-value for difference between treatments.3–18.7 10.4) (5.0) (43.8 (15.9) (3.0005 0.2) (10. after treatment with a single dose of rabeprazole or pantoprazole on day 1 (bottom).0003 (10.6 (6.3–11.0–50.9) (16.8–37. Individual subjects’ data for percentage time pH > 4 over 24 h at baseline on day 0 (top).5) (34.1 17.1 42.1 8.5 3.6 36.0001 0 Rabeprazole 20 mg 100 90 Pantoprazole 40 mg pH > 4 0 0–14 14–24 0–24 0–14 14–24 0–24 12.6 28. as shown by vital ª 2007 The Authors.4) (18.8–47.003 <0.016 0.1–28.1) (1.3–27. Mean (95% CI) intragastric pH AUC at baseline (day 0) and after a single dose of rabeprazole 20 mg or pantoprazole 40 mg (n ¼ 29) Mean (95% CI) intragastric pH AUC Day 0 Interval (h) 0–5 5–11 11–14 14–24 0–24 0–5 5–11 11–14 14–24 0–24 Rabeprazole 20 mg 40 43 25 71 180 57 94 52 115 319 675 477 540 156 849 327 894 283 096 692 (36 230–45 120) (37 754–49 200) (22 093–28 988) (60 523–81 790) (162 856–198 842) (51 868–62 786) (83 874–105 914) (46 537–58 030) (100 089–130 103) (291 431–347 952) Pantoprazole 40 mg 41 42 23 58 166 51 72 40 94 259 707 852 332 398 289 468 604 970 863 921 (36 626–46 787) (36 849–48 855) (20 372–26 292) (52 393–64 402) (151 342–181 237) (46 458–56 479) (63 882–81 327) (36 567–45 374) (82 887–106 839) (234 674–285 168) P-value* 1 0.2 14.8–45. from linear mixed-effect analysis with day 0 value in model as a covariate.1–36.1) <0. Safety Single oral doses of rabeprazole 20 mg and pantoprazole 40 mg were safe and well tolerated in GERD patients with nocturnal heartburn.2–17.7 17.2) 12.004 (21.2–24. Aliment Pharmacol Ther 25.8–18.4 (6.2 8.9 39.6) 0.5–61.7–50.4) (5.9) (56.0) (6.8 25.0) (46.001 0. 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd Figure 2.4 39.5) (29.0 5.6) (41. P A N T O P R A Z O L E I N G E R D P A T I E N T S 515 Table 1.0001 Day 1 (0–24 h) 80 Percent time pH >4 70 60 50 40 30 20 10 0 Rabeprazole 20 mg Pantoprazole 40 mg 1 * P-value for difference between treatments.4 49. .4) P-value* 100 90 80 Percent time pH >4 70 60 50 40 30 20 10 Day 0 (0–24 h) 1 0.4–14.8–34.1–5.9) (27.6–22.0005 0.8–18.5) 0.1) Pantoprazole 21.

9% of subjects. therefore. in which single doses of rabeprazole 10 mg yielded a significantly greater acid suppressant effect than did pantoprazole 40 mg or omeprazole 20 mg. However.6% of events).6 As the acid suppressant effect of rabeprazole 20 mg significantly exceeded that of pantoprazole 40 mg. oral rabeprazole was pharmacologically more than twice as potent as oral pantoprazole on an mg-per-mg basis. it is clear that in our study population. and gastrointestinal disturbances.8. Our results are consistent with those of a previous study in healthy H. physical examination. pylori-negative volunteers. Such use requires a PPI with a substantial effect on intragastric pH that is sustained over the 24 h after a single dose. Most of these events were mild. we do not believe that the open design is a serious limitation. Only one study has directly compared the pharmacodynamic effects of repeated doses of rabeprazole and pantoprazole. DISCUSSION Overall. Aliment Pharmacol Ther 25. 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. W A R R I N G T O N et al. 13. ideally. the first dose should have a profound effect. 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. 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. signs. laboratory safety tests and adverse events. the endpoint.1% of events). mean percentage time pH > 4 was significantly higher after rabeprazole than pantoprazole during the 24 h after dosing and in all time intervals analysed. Studies of on-demand use of rabeprazole suggest that it controls symptoms effectively. adverse events after both rabeprazole and pantoprazole were headache (41.9 National guidelines ª 2007 The Authors. lansoprazole 30 mg or omeprazole 20 mg.4 Furthermore.4 Our results are also compatible with those of a study in patients with gastric or duodenal ulcer. as part of a crossover study comparing five PPIs in GERD patients. the authors did not present the statistical significance of the differences. Consistent with clinical experience. including indigestion. However. intragastric pH. 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. after treatment with a single dose of rabeprazole or pantoprazole on day 1 (bottom) . nausea and abdominal discomfort (25. 12-lead ECG. Individual subjects’ data for percentage time pH > 4 during night (14–24 h) at baseline on day 0 (top). 27.8% of subjects. and during each time interval (including the overnight hours). as judged by nocturnal acid breakthrough and nocturnal alkaline amplitude. Our findings may also be relevant to the intermittent or on-demand use of rabeprazole in uncomplicated GERD. 100 90 80 Percent time pH >4 70 60 50 40 30 20 10 0 Rabeprazole 20 mg 100 90 80 Percent time pH >4 70 60 50 40 30 20 10 0 Rabeprazole 20 mg Pantoprazole 40 mg Pantoprazole 40 mg Day 0 night (14–24 h) Day 1 night (14–24 h) Figure 3. Our results are of potential clinical relevance to the use of rabeprazole at the start of continuous therapy in symptomatic patients with GERD.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. when. One possible limitation of our study is its open-label design. However. In addition. 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd . it should be noted that the results reported here apply only to single doses of the drugs. is an objective measurement.516 S .

Baisley K. ACKNOWLEDGEMENT Authors’ declaration of personal interests: K. Jornod P. Sostek M.to 24h period. 20 mg. 3 Orr WC. In summary.2 h vs. 8 Bytzer P. pantoprazole. REFERENCES 1 Bell NJ. Chen Y. Bastida G. not only because it promotes patients’ involvement in the management of their disease.. 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. Ortiz V. August 2004. in patients with GERD and nocturnal heartburn. Unit of Ortho-McNeil Inc. and rabeprazole: a five-way crossover study. clinical trials would be needed to test that expectation. In our study. Dorta G. Katz PO. Aliment Pharmacol Ther 1995. 51 (Suppl. Blum AL. Am J Gastroenterol 2003. Effect of a single oral dose of rabeprazole on nocturnal acid breakthrough and nocturnal alkaline amplitude. 1): 59–67. Niu CY. Lomax is an employee of Eisai Inc.R A B E P R A Z O L E V S . Dubois D. B. and patient satisfaction. Declaration of funding interests: the study was funded in full by Eisai Inc. 49: 931–6. Aliment Pharmacol Ther 25. Effects of rabeprazole. World J Gastroenterol 2003. 17: 1507–14. 10 National Institute of Clinical Excellence (NICE). 5 Warrington S. hazards. Gastric acid control with esomeprazole. De Herdt D. 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. Aliment Pharmacol Ther 2004. If GERD patients were to take a single dose of these drugs during the first half of the day. 9 (Suppl. 20 mg. P A N T O P R A Z O L E I N G E R D P A T I E N T S 517 in the UK now recommend on-demand therapy for GERD. Wilkinson J. Although pantoprazole has a slightly longer half-life than rabeprazole (1. on 24-h intragastric pH and serum gastrin in healthy subjects. omeprazole. These doses are the ones currently recommended for use in GERD. Night-time gastro-oesophageal reflux disease: prevalence. 511–517 Journal compilation ª 2007 Blackwell Publishing Ltd . but also because it should be less expensive. 7 Miner P Jr. Wang XQ. Delemos is an employee of Pricara. Boyce M. rabeprazole might be expected to be the more effective treatment in preventing nocturnal heartburn. On-demand therapy with rabeprazole in nonerosive and erosive gastroesophageal reflux disease in clinical practice: effectiveness. Six-month trial of on-demand rabeprazole 10 mg maintains symptom relief in patients with non-erosive reflux disease. However. by the oral route.10 Relief of nocturnal reflux requires a medication with an acid suppressant effect that is sustained into the overnight hours. USA and Pricara. Garrigues V. health-related quality of life. 4 Pantoflickova D. Ravic M.0 h). lansoprazole. Aliment Pharmacol Ther 2002. Acid inhibition on the first day of dosing: comparison of four proton pump inhibitors.4 tablets/day. Morocutti is an employee of Eisai Ltd. Eur J Gastroenterol Hepatol 2005. 20: 181–8. Hunt RH. or esomeprazole. Arguello L. Howden CW. 1): 3–7. 9: 2583–6. 16: 1301–7. ª 2007 The Authors. we found the effect of rabeprazole on intragastric pH to be more sustained. Miller N. Zhu YL. 9 Ponce J. 2 Hunt RH. 98: 2616–20. Digestion 1992. Clinical guideline on management of dyspepsia in adults in primary care. Morocutti A. A. 17: 113–20. Dig Dis Sci 2004. Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Burget D. Rabeprazole was pharmacologically more potent than pantoprazole. Aliment Pharmacol Ther 2003. Tejura B. and management. 6 Luo JY. Blum A. Gong J. The relationship between the control of pH and healing and symptom relief in gastro-oesophageal reflux disease. 1. as patients take an average of 0. The difference between treatments was most marked in the 5. Ponce M. including night time. 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.