Rabeprazole is superior to omeprazole for the inhibition of peptone meal-stimulated gastric acid secretion in Helicobacter pylori-negative subjects

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1 Aliment Pharmacol Ther 2003; 17: doi: /j x Rabeprazole is superior to omeprazole for the inhibition of peptone meal-stimulated gastric acid secretion in Helicobacter pylori-negative subjects G. V. OHNING, J. H. WALSH, J. R. PISEGNA, A. MURTHYà, J. BARTHà & T. O. G. KOVACS Research and Medical Services, Department of Veteran Affairs, VA GLAHS-West Los Angeles Healthcare Center, and the Department of Medicine, School of Medicine, and CURE/UCLA Digestive Disease Center, University of California, Los Angeles, CA, USA; àeisai Inc., Teaneck, NJ, USA Accepted for publication 19 September 2002 SUMMARY Background: Peptone meal-stimulated gastric acid output is considered to be a reliable means to evaluate drug-mediated inhibition of stimulated gastric acid output, an important measure of the efficacy of the agents such as proton pump inhibitors used to treat acid-related disorders. Aim: To compare the initial and overall inhibitory effects on peptone meal-stimulated gastric acid secretion of rabeprazole and omeprazole, 20 mg, in Helicobacter pylori-negative subjects on the first and eighth days of treatment. Methods: Healthy volunteers (n ¼ 27) were randomized in a single-centre, double-blind, double-dummy, 2 2 cross-over study. Subjects received an oral dose of rabeprazole or omeprazole, 20 mg once daily, for 8 days. After a 2 4-week washout period, subjects were crossed over to receive the other medication for 8 days. Peptone meal-stimulated gastric acid secretion was measured at hours 11 and 23 at baseline and on days 1 and 8 of treatment. Results: On days 1 and 8, rabeprazole demonstrated a significantly greater inhibition of peptone meal-stimulated gastric acid secretion compared with omeprazole at all time points (P < 0.03). Median values of steadystate inhibition on day 1 were statistically significant at hour 23 (rabeprazole 100% vs. omeprazole 74%, P < 0.02). Conclusions: Rabeprazole, 20 mg, demonstrated superior control of peptone meal-stimulated gastric acid secretion compared with omeprazole, 20 mg, after the first dose and after the eighth daily dose. Rabeprazole achieved a more rapid onset of acid inhibition and a greater steady-state reduction in peptone meal-stimulated gastric acid secretion. INTRODUCTION The control of gastric acid secretion is important in the initial and long-term treatment of peptic disorders of the upper gastrointestinal tract, particularly gastro-oesophageal reflux disease. Rabeprazole is a member of the Correspondence to: Dr G. V. Ohning, CURE Digestive Disease Research Center, VA GLAHS-West Los Angeles Healthcare Center, Bldg. 115, Rm 217, Wilshire Blvd., Los Angeles, CA 90073, USA. gohning@ucla.edu Deceased. family of substituted benzimidazole proton pump inhibitors that act by forming a covalent bond to the alpha subunit of H +,K + -adenosine triphosphatase (H +,K + - ATPase), effectively inhibiting gastric acid secretion from the parietal cell. 1 The efficacy of proton pump inhibitors can be expressed by the degree and duration of acid suppression per 24-h period after administration and for the overall duration of treatment. 1 We have previously shown rabeprazole s rapid, potent and long-lasting inhibitory effects on gastric acid secretion in Helicobacter Ó 2003 Blackwell Publishing Ltd 1109

2 1110 G. V. OHNING et al. pylori-positive subjects. 2 In the present study, the effectiveness of rabeprazole was compared with omeprazole in the inhibition of peptone meal-stimulated gastric acid secretion after the initiation of therapy and after 8 days of treatment in H. pylori-negative subjects. We excluded H. pylori-positive subjects because H. pylori infection has been shown to enhance the efficacy of proton pump inhibitor therapy. Peptone meal-stimulated gastric acid secretion was determined by an intragastric titration method. 3 This technique measures gastric acid output during physiological stimulation with nutrients, 4 allowing for the comparison of proton pump inhibition in a clinically relevant and reproducible model of stimulated gastric acid secretion. MATERIALS AND METHODS Subjects The research protocol was reviewed and approved by the University of California Los Angeles Institutional Review Board (IRB ) prior to study initiation, and the study was conducted in compliance with all Board regulations. All subjects gave written informed consent before participating in the study. Thirty subjects were enrolled and 27 completed the study. The subjects were screened for enrollment by complete history and physical examination, clinical laboratory tests and gastric acid analysis within a 4-week period prior to baseline acid secretion measurements (day 0). To qualify, subjects were required to have a peptone meal-stimulated gastric acid secretion rate of 8 mmol/h. All subjects were required to have a negative test for H. pylori by serology and to have no previous history of H. pylori infection. Subjects were excluded from the study if they had a history of gastric surgery, abnormal bleeding, thrombophlebitis, human immunodeficiency virus, hepatitis B or hepatitis C infection, any concurrent illnesses or any pre-existing condition that might interfere with any process of the drug from absorption to excretion, any clinically significant substance abuse or psychiatric risk, known hypersensitivity to omeprazole or rabeprazole or the use of histamine 2 -receptor antagonists, prostaglandin analogues, sucralfate, any proton pump inhibitors or any investigational agent within 30 days of study initiation. Female subjects of child-bearing potential were required to use an acceptable method of birth control and to have a negative pregnancy test result prior to study entry and before each treatment period. Study design This study was a single-centre, randomized, doubleblind, double-dummy, 2 2 cross-over design. In the initial baseline period (day 0), after an 8-h overnight fast, subjects received double placebo oral formulations of the study drugs; only low-fat liquids were allowed for 2 h after placebo dosing, following which subjects ate only low-fat, low-fibre foods. They then fasted for at least 6 h until peptone meal-stimulated gastric acid secretion was measured at hour 11. At hour 12, a standard meal was given, and subjects then fasted from hour 15 to hour 23 (8 h), at which time peptone mealstimulated gastric acid secretion was again measured. The first treatment period was initiated within 2 weeks following the baseline day. Subjects were treated for eight consecutive days with one active and one placebo formulation of the study drugs (rabeprazole and omeprazole). All medications were administered orally every morning. Peptone meal-stimulated gastric acid secretion was measured at hours 11 and 23 post-dose on days 1 and 8 of treatment. As during the baseline day, on each study day, subjects fasted for 8 h prior to dose administration and the hour 23 gastric secretion measurement and for 6 h prior to the hour 11 gastric secretion measurement. After a 2 4-week washout period, subjects entered the cross-over treatment period, during which the same procedures were followed as in the first treatment period. One post-treatment visit was conducted within 2 weeks of completion of the second study period to assess the subjects for adverse events and to obtain an exit physical examination and laboratory testing. Compliance with study drug administration was determined by pill count from the administered blister package. Measurement of peptone meal-stimulated gastric acid secretion Each subject was seated in a slightly recumbent chair, and a double-lumen gastric tube (ANPRO AN10, H.W. Anderson Products Inc., Haw River, NC, USA) was placed and positioned. After gastric tube placement, 600 ml of an 8% peptone meal (adjusted to ph 5.5, 320 mos/l; Bactopeptone, Difco Laboratories Inc., Detroit, MI, USA) was infused by gravity over

3 RABEPRAZOLE IS SUPERIOR IN THE INHIBITION OF ACID SECRETION min. Gastric acid secretion was measured using intragastric titration of acid with standardized 0.1 n sodium hydroxide (EM Science, Gibbstown, NJ, USA) to maintain the intragastric ph at 5.5 for a 1-h period. The gastric contents were continuously sampled using an automatic pipetting machine (Scientific Equipment Products, Baltimore, MD, USA), and the gastric ph was measured and adjusted using an ABU901 Autoburette and PHM290 ph-stat controller (Radiometer America, Copenhagen Instruments, Cleveland, OH, USA). The amount of 0.1 n NaOH added during hour 1 of titration was used to calculate the acid output. Gastric acid outputs per hour were reported as the mean values for the baseline and treatment groups. The mean percentage inhibition of acid secretion for each group was calculated from the percentage inhibition for individual subjects. Statistical methods Statistical analyses were performed using SAS software version 6.12 or higher (SAS Institute, Cary, NC, USA), and all tests performed were two-tailed and conducted at the P 0.05 level of significance. An analysis of variance (anova) appropriate for a 2 2 cross-over study was used for the analysis of continuous variables, and the Cochran Mantel Haentzel test and Fisher s exact test were used for the analysis of categorical variables. Adverse events were assessed by the incidence of treatment of emergent signs and symptoms, and these events were classified by body system class and COSTART (Coding Symbols for a Thesaurus of Adverse Reaction Terms) preferred terminology. RESULTS Subjects Twenty-seven subjects qualified for the study, with 24 completing dosing with rabeprazole and 25 completing omeprazole dosing. The randomized distribution resulted in 11 rabeprazole- and 14 omeprazole-treated subjects during the first drug treatment period, and 13 rabeprazole- and 11 omeprazole-treated subjects during the second drug treatment period. Three subjects discontinued participation for reasons unrelated to the study drug: one subject received only a baseline placebo dose and no active medication; a second subject left after only one dose of rabeprazole during the first treatment period; and Table 1. Subject demographics Characteristic n ¼ 27 Sex, n (%) Male 17 (63.0) Female 10 (37.0) Race, n (%) White 20 (74.1) Black 1 (3.7) Hispanic 3 (11.1) Asian/Pacific Islander 2 (7.4) Other 1 (3.7) Mean age (years) 30.4 Mean weight (kg) 74.8 Mean height (cm) a third subject completed the full omeprazole course of therapy but received no rabeprazole treatment. Four individual measurements were excluded from the intention-to-treat analysis due to equipment failure. Subject demographics are shown in Table 1. Peptone meal-stimulated gastric acid output Rabeprazole reduced peptone meal-stimulated gastric acid secretion, expressed as the mean percentage acid inhibition, to a significantly greater degree than omeprazole at all time points on day 1; reductions were also significantly greater with rabeprazole than with omeprazole on day 8 at all time points. Specifically, after initial dosing on day 1, rabeprazole inhibited peptone meal-stimulated gastric acid secretion by 72% at hour 11 and 64% at hour 23, compared with an inhibition of 49% at hour 11 and 38% at hour 23 for omeprazole (P < 0.03, rabeprazole vs. omeprazole, both time points). On day 8, inhibition with rabeprazole was 88% at hour 11 and 64% at hour 23, whereas omeprazole-treated subjects demonstrated 78% inhibition at hour 11 and 50% inhibition at hour 23 (P < 0.03, rabeprazole vs. omeprazole, both time points). Data were reported as the mean inhibition of gastric acid output for each group calculated from the percentage inhibition for individual subjects (Figure 1). In addition, rabeprazole treatment was shown to result in significantly lower levels of peptone meal-stimulated gastric acid secretion (as measured in mmoles of acid) than omeprazole treatment at all time points on days 1 and 8 (P < 0.015; Table 2). The median values of maximal acid inhibition on day 1 demonstrated that rabeprazole achieved 91% of

4 1112 G. V. OHNING et al. 100 Rabeprazole 20 mg Omeprazole 20 mg 100 Rabeprazole 20 mg Omeprazole 20 mg Mean inhibition (%) Median inhibition (%) Hour 11 Hour 23 Hour 11 Hour 23 Day 1 Day 8 0 Hour 11 Hour 23 Day 1 Figure 1. Comparison of the mean inhibition of peptone mealstimulated gastric acid output for rabeprazole, 20 mg, and omeprazole, 20 mg, at hours 11 and 23 on days 1 and 8 of treatment. The mean inhibition for each group was calculated from the percentage inhibition for individual subjects. Table 2. Mean (± S.E.) peptone meal-stimulated gastric acid secretion (mmoles of acid) on days 1 and 8 of treatment Baseline (1.46) Rabeprazole 6.24 (1.58) Omeprazole (2.01) P < vs. omeprazole. steady-state inhibition at hour 11 and 100% at hour 23. The values for omeprazole were 68% at hour 11 and 74% at hour 23 (Figure 2). The difference was statistically significant at hour 23 (P < 0.02). Adverse events Day 1 Day 8 Hour 11 Hour 23 Hour 11 Hour (1.55) 5.86 (1.18) 9.59 (0.98) (1.39) 2.26 (0.46) 4.50 (0.91) (1.59) 6.28 (1.09) 8.02 (1.11) Both medications were well tolerated, as determined by clinical assessment and laboratory values. No serious adverse events were reported. At least one adverse event occurred in 80% of rabeprazole-treated subjects and 68% of omeprazole-treated subjects. The majority (86%) of the adverse events reported were mild in severity; 14% were considered to be moderate in severity. No subjects discontinued study participation because of an adverse event. Headache was the most commonly Figure 2. Median percentage of maximal inhibition of peptone meal-stimulated gastric acid secretion attained on day 1. Comparison of the percentage of maximal inhibition of rabeprazole, 20 mg, and omeprazole, 20 mg, at hours 11 and 23 on the first day of dosing. reported adverse event by both groups [40% (10/25) of rabeprazole-treated subjects; 32% (8/25) of omeprazole-treated subjects]. Adverse events that were considered to be related to treatment accounted for 45% of the symptoms reported by the rabeprazole group and 44% of those reported by the omeprazole group. DISCUSSION Rabeprazole is a substituted benzimidazole proton pump inhibitor with a potent and long-acting inhibitory effect on gastric acid secretion. Rabeprazole has been shown to have a more rapid onset of action than omeprazole in reducing gastric acidity. 5, 6 We have previously reported the inhibition of gastric acid secretion with rabeprazole in H. pylori-positive subjects. 2 In this study, the efficacy of rabeprazole compared with omeprazole was determined by measuring peptone meal-stimulated gastric acid output in H. pylori-negative subjects immediately after initial treatment and during steady state. Nutrients provide a physiological stimulation of gastric acid secretion, 3 and the use of the peptone meal allows for intragastric titration of acid and the reproducible determination of peptone meal-stimulated gastric acid output. 4 This method provides a reliable and validated measurement of the drug-mediated inhibition of stimulated gastric acid output. Peptone meal-stimulated gastric acid output has been used previously to evaluate the efficacy of omeprazole treatment. The inhibitory effect of omeprazole

5 RABEPRAZOLE IS SUPERIOR IN THE INHIBITION OF ACID SECRETION 1113 demonstrated in the present study is similar to that described in a previous report, which showed 42%, 80% and 92% inhibition of peptone meal-stimulated gastric acid secretion for single doses of 30 mg, 60 mg and 90 mg of omeprazole, respectively. 7 Another trial showed a 90% decrease in 24-h intragastric acidity after 1 week of treatment with 20 mg of omeprazole in patients with duodenal ulcer who received six identical meals spaced at 3-h intervals during waking hours. 8 In the present study, both rabeprazole and omeprazole demonstrated a marked inhibition of peptone mealstimulated gastric acid secretion at hours 11 and 23 on days 1 and 8; however, rabeprazole demonstrated a significantly greater inhibitory effect at all time points compared with omeprazole (Figure 1). The study was designed to measure the inhibition of gastric acid output just prior to the mid-point between daily doses (hour 11), and the antisecretory effect just prior to the next daily dose (hour 23). At hour 11 post-dose, rabeprazole achieved 91% of its maximal inhibitory effect on mealstimulated gastric acid secretion on the first day of treatment (day 1), compared with 68% for omeprazole; at hour 23, the values were 100% and 74% for rabeprazole and omeprazole, respectively, a significant difference (Figure 2). Overall, these data indicate that rabeprazole achieves a significantly greater degree of inhibition of gastric acid secretion after the first dose of medication, and the effect is maintained at steady state during subsequent daily dosing over an 8-day period. These data correlate well with a recent report of rabeprazole-mediated inhibition of gastric acidity, measured by continuous ph monitoring, in patients with clinical gastro-oesophageal reflux disease, in that maximal gastric acid output was rapidly and profoundly inhibited after the first dose of medication. 9 The clinical efficacy and tolerability of rabeprazole have been well documented. Rabeprazole, 20 mg, has been shown to be highly efficacious in healing gastric ulcers, duodenal ulcers and gastro-oesophageal reflux disease in a report of three multicentre studies. 10 In a European multicentre study of 103 patients at 25 sites, rabeprazole, 20 mg, and omeprazole, 20 mg, were evaluated in the treatment of duodenal ulcer. After 4 weeks of treatment, a similar rate of ulcer healing was achieved with rabeprazole (98%) and omeprazole (93%); however, rabeprazole-treated subjects reported significantly greater improvements in daytime pain than did omeprazole-treated subjects (P < 0.05; all other symptomatic parameters were comparable in both groups). Initially, mean changes from baseline in fasting serum gastrin were significantly greater in the rabeprazole group; however, the mean values at the end-point were within normal limits for both groups. Both drugs showed good tolerability. 11 A very recent investigation comparing rabeprazole, 20 mg, and esomeprazole, 20 mg, showed that, on a milligram-permilligram basis, rabeprazole increased the 24-h ph on day 1 of dosing to a greater degree than did esomeprazole in healthy subjects, 12 although at standard doses in patients with symptoms of gastro-oesophageal reflux disease an opposite finding has been reported. 13 These and other studies demonstrate that rabeprazole is safe and well tolerated, with a favourable risk/benefit profile. 14 Rabeprazole has the highest pk a value of the proton pump inhibitors and is therefore the least stable at neutral ph. 15 Our previous report demonstrated a prolonged inhibitory effect in H. pylori-positive subjects, 2 and the present study also demonstrates a significantly greater inhibition of acid secretion at 23 h after dosing compared with omeprazole. This suggests that rabeprazole achieves greater efficacy by blocking more of the proton pumps following dosing. Previous studies in healthy human subjects have demonstrated that a significantly greater increase in 24-h intragastric ph is achieved with rabeprazole than with lansoprazole, pantoprazole, omeprazole and placebo (P ¼ 0.04). 6 In addition, rabeprazole was significantly superior to omeprazole at maintaining intragastric ph > 3.0 (69% vs. 59%, P < 0.01) and ph > 4.0 (60% vs. 51%, P < 0.05) after eight consecutive days of treatment. 16 The relationship between the chemical properties of rabeprazole and its clinical effectiveness might be explained by the properties of the covalent bond to the transmembrane regions of the proton pump. Rabeprazole demonstrated the fastest rate of inhibition of in vitro ATPase activity in gastric vesicles when compared with omeprazole, lansoprazole and pantoprazole. 15 Furthermore, rabeprazole demonstrated continued binding to several transmembrane domains after achieving 100% inhibition of both ATPase activity and acid transport. 15 These effects may account for the more potent and prolonged efficacy of rabeprazole reported in studies in humans. Rabeprazole demonstrated a significantly greater inhibition of peptone meal-stimulated gastric acid secretion with the first dose and on the eighth day of daily treatment compared with omeprazole in H. pylori-negative

6 1114 G. V. OHNING et al. subjects. Rabeprazole was able to achieve % of its maximal inhibitory effect after a single dose, demonstrating its rapid onset and potent ability to inhibit peptone meal-stimulated gastric acid secretion. These data suggest that rabeprazole is a highly effective treatment for peptic disorders, and that its antisecretory effect is near maximal with the first dose. ACKNOWLEDGEMENTS This work was supported by Eisai Inc., Teaneck, NJ, USA and Janssen Pharmaceutica Inc., Titusville, NJ, USA and, in part, by the UCLA Clinical Research Center (NIH MOI-RR-00865). REFERENCES 1 Williams MP, Pounder RE. Review article: the pharmacology of rabeprazole. Aliment Pharmacol Ther 1999; 13(Suppl. 3): Ohning GV, Barbuti RC, Kovacs TOG, et al. Rabeprazole produces rapid, potent, and long-acting inhibition of gastric secretion in subjects with Heliobacter pylori infection. Aliment Pharmacol Ther 2000; 14: Fordtran JS, Walsh JH. Gastric acid secretion rate and buffer content of the stomach after eating. Results in normal subjects and in patients with duodenal ulcer. J Clin Invest 1973; 52: Maxwell V, Eysselein VE, Kleibeuker J, Reedy T, Walsh JH. Glucose perfusion intragastric titration. Dig Dis Sci 1984; 29: Williams MP, Sercombe J, Hamilton RE, et al. A placebocontrolled trial to assess the effects of 8 days of dosing with rabeprazole versus omeprazole on 24-h intragastric acidity and plasma gastrin concentrations in young healthy subjects. Aliment Pharmacol Ther 1998; 12: Pantoflickova D, Dorta G, Jornod P, Blum AL. Antisecretory activity of PPIs. Gut 2000; 47(Suppl. 3): A64(Abstract). 7 Londong W, Londong V, Cederburg C, et al. Dose response study of omeprazole on meal-stimulated gastric acid secretion and gastrin release. Gastroenterology 1983; 85: Sharma BK, Walt RP, Pounder RE, Gomes MD, Wood EC, Logan LH. Optimal dose of oral omeprazole for maximal 24 hour decrease of intragastric acidity. Gut 1984; 25: Gardner JD, Perdomo C, Sloan S, et al. Integrated acidity and rabeprazole pharmacology. Aliment Pharmacol Ther 2002; 16: Cloud ML, Enas N, Humphries TJ, et al. Rabeprazole in treatment of acid peptic diseases: results of three placebo-controlled dose response clinical trials in duodenal ulcer, gastric ulcer, and gastroesophageal reflux disease (GERD). Dig Dis Sci 1998; 43: Dekkers CPM, Beker JA, Thjodleifsson B, et al. Comparison of rabeprazole 20 mg versus omeprazole 20 mg in the treatment of active duodenal ulcer: a European multicenter study. Aliment Pharmacol Ther 1999; 13: Baisley KJ, Tejura B, Morocutti A, Miller NM, Warrington S. Rabeprazole 20 mg is more potent than esomeprazole 20 mg in control of gastric ph in healthy volunteers. Am J Gastroenterol 2001; 96(Suppl. 1): S Wilder-Smith C, Claar-Nilsson C, Hasselgren G, Röhss K. Esomeprazole 40 mg provides faster and more effective acid control than rabeprazole 20 mg in patients with symptoms of GERD. Am J Gastroenterol 2001; 96(Suppl.): S Johnson P, Perdomo C, Barth J, Jokubaitis L. The benefit/risk profile of rabeprazole, a new proton pump inhibitor. Eur J Gastroenterol Hepatol 2000; 12: Besancon M, Simon A, Sachs G, et al. Sites of reaction of the gastric H,K-ATPase with extracytoplasmic thiol reagents. J Biol Chem 1997; 272: Williams MP, Blanshard C, Millison J, et al. A placebo-controlled study to assess the effects of 7-day dosing with 10, 20 and 40 mg rabeprazole on 24-h intragastric acidity and plasma gastrin in healthy male subjects. Aliment Pharmacol Ther 2000; 14: