Intragastric acidity during treatment with esomeprazole 40 mg twice daily or pantoprazole 40 mg twice daily a randomized, two-way crossover study

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1 Aliment Pharmacol Ther 2005; 21: doi: /j x Intragastric acidity during treatment with esomeprazole 40 mg twice daily or pantoprazole 40 mg twice daily a randomized, two-way crossover study S. MIEHLKE*, A. MADISCH*, C. KIRSCH*, F. LINDNER*, E. KUHLISCH, M. LAASSà, H. KNOTH, A. MORGNER* & J. LABENZ *Medical Department I, Technical University Hospital Dresden, Germany; Institute for Medical Biometry, Technical University Hospital Dresden, Germany; àchildren s Hospital, Technical University Hospital Dresden, Germany; Department of Pharmacy, Technical University Hospital Dresden, Germany; Medical Department, Jung-Stilling Hospital, Siegen, Germany Accepted for publication 6 February 2005 ABSTRACT Background: Patients with severe or complicated reflux disease may require higher than standard doses of a proton pump inhibitor for sufficient acid suppression. Aim: To test the hypothesis that esomeprazole 40 mg twice daily is superior to pantoprazole 40 mg twice daily in lowering intragastric acidity. Methods: In a randomized, single-blinded, two-way crossover study, healthy subjects received esomeprazole 40 mg twice daily or pantoprazole 40 mg twice daily orally for five consecutive days. Continuous ambulatory 24-h intragastric ph was recorded on day 5 of each treatment. Results: Thirty subjects were analysed. Esomeprazole provided significantly higher intragastric ph-values over the 24-h period [median intragastric ph 6.4 for esomeprazole and 5.1 for pantoprazole (P < )]. Intragastric ph > 4 was maintained for 21.1 h with esomeprazole and 16.8 h with pantoprazole (P < ). An intragastric ph > 4 for more than 16 h was achieved in 96.7 and 56.7% of subjects, respectively (P ¼ ). During night-time the proportion of time with intragastric ph > 4 was 85.4% with esomeprazole and 63.6% with pantoprazole (P ¼ ). Nocturnal acid break through occurred less frequently on esomeprazole. Conclusions: Esomeprazole 40 mg twice daily provides better and more consistent intragastric acid control than pantoprazole 40 mg twice daily. INTRODUCTION Proton pump inhibitors (PPI) are currently the most effective drugs for the treatment of acid related disorders like gastro-oesophageal reflux disease (GERD). 1 Profound and consistent suppression of gastric acid is important in the treatment of GERD, as the healing of erosive oesophagitis is directly related to the time spent with an intragastric ph above 4. 2, 3 Correspondence to: Dr S. Miehlke, Medical Department I, Technical University Hospital, Fetscherstr. 74, Dresden, Germany. stephan.miehlke@uniklinikum-dresden.de However, some patients with severe reflux oesophagitis may not respond adequately to standard dose PPI treatment. 4 Moreover, healing of erosive oesophagitis is even more hampered in patients with Barrett oesophagus and without Helicobacter pylori infection. 5, 6 Thus, a considerable fraction of patients with GERD may require higher than standard dose PPI to increase the intragastric ph above 4 for more than two-third of the day. In the case of pantoprazole, doubling the individual PPI did not improve the clinical outcome in patients with erosive oesophagitis. 7 Crossover studies in both healthy subjects and GERD patients have shown that esomeprazole at standard dose Ó 2005 Blackwell Publishing Ltd 963

2 964 S. MIEHLKE et al. (40 mg) and maintenance dose (20 mg) produces a significantly greater amount of time with an intragastric ph greater 4 than respective doses of all other PPIs The improved gastric acid suppression provided by esomeprazole translates into clinical benefit, as esomeprazole was superior to other PPIs in terms of the healing and maintenance of erosive oesophagitis The aim of this study was to compare the effect of esomeprazole 40 mg twice daily and pantoprazole 40 mg twice daily on intragastric ph at steady state. We tested the hypothesis that orally administered double-dose esomeprazole is superior to double-dose pantoprazole in elevating the intragastric ph. MATERIALS AND METHODS Subjects Healthy men and women between 18 and 60 years of age, recruited by local advertisement within the University Hospital, were eligible for enrolment. The subjects were considered healthy based on a detailed medical history, physical examination, and routine laboratory evaluation. Only subjects who were H. pylori negative based on 13 CO 2 urea breath test (INFAI, Cologne, Germany) were eligible. Subjects with past or present significant clinical illness and those with known intolerance to approved PPIs were excluded. Women with childbearing potential were required to use acceptable birth control methods. Further exclusion criteria were pregnancy, lactation, abnormal laboratory values at baseline, drug or alcohol abuse. Antisecretory drugs including PPIs, H2-receptor antagonists, prokinetic drugs or any other agents that could affect the pharmacokinetics or absorption of PPIs were not allowed during the study or within 2 weeks before randomization. All subjects gave written informed consent prior to enrolment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The study was approved by the local institutional review board at the University Hospital Carl Gustav Carus, Technical University Dresden. Study design and procedures In this randomized, investigator-blinded, two-way crossover study each subject received either esomeprazole 40 mg twice daily or pantoprazole 40 mg twice daily for five consecutive days according to a computer-generated randomization list. Crossover therapy followed after a washout period of 14 days (±3 days). The study medication was placed in identically looking white screw-cap plastic container and given to the subject by a study coordinator prior to each treatment period. Subjects were carefully instructed to swallow one unchewed tablet in the morning between 7 and 8 am together with 200 ml of water 30 min before meal, and one unchewed tablet 12 h later 30 min before meal, for five consecutive days. Subjects were further instructed to avoid smoking and alcohol consumption during the entire treatment period and to lie down only at nighttime hours between 10 pm and 6 am. They were also encouraged to report adverse events spontaneously. Drug compliance and tolerability was assessed by interview and pill count at the end of day 5 of each treatment period. Routine laboratory examinations including haematology and clinical chemistry were performed at the screening visit and on day 5 of each treatment period. Assessment of intragastric ph An ambulatory continuous 24-h intragastric ph recording was performed beginning on day 5 of each treatment period. A calibrated microelectrode was positioned 10 cm below the manometrically located lower oesophageal sphincter at 7.30 am prior to breakfast and administration of the study drug and removed the following morning before 8 am. The electrode was calibrated before and after each recording. Intragastric ph was evaluated every 4 s and recorded on the attached Digitrapper MKIII (Medtronic GmbH, Düsseldorf, Germany). All ph measurements were blinded and assessed by a single gastroenterologist independent of the principle investigator. Statistics We analysed data from a two-treatment, two-period (2 2) cross-over design using a random effects model modelling the carryover effect from one period to the next, the treatment (drug) effect and the period effect. First the assumptions of using a cross over design were tested. The results showed that there was neither a carryover effect from one period to the next nor a period effect for all of the investigated measures.

3 TWICE-DAILY ESOMEPRAZOLE VS. PANTOPRAZOLE 965 P-values <0.05 were considered significant. Results are given as averaged means and their difference, including the 95% confidence interval. RESULTS Subject characteristics Forty-seven Caucasian subjects were screened. Thirteen subjects were excluded because of positive H. pylori status (n ¼ 5) or disagreement with the study protocol (n ¼ 8). Thirty-four subjects were randomized into the study. Another four subjects were excluded during the study because of technical problems or premature discontinuation of ph monitoring because of discomfort. In total, 30 volunteers (15 women) completed both dosing periods and provided complete ph monitoring data for further analysis. The mean age was 25 years (19 47 years). The mean body mass index was 21.7 ( ) kg/m 2. Intragastric ph The mean number of hours with available ph data was 23.6 h ( ) with esomperazole and 23.8 h ( ) with pantoprazole. Esomeprazole provided higher intragastric ph values throughout the 24-h period (Figure 1), with the median intragastric ph being 6.4 under esomeprazole and 5.1 under pantoprazole (P < ). The intragastric ph was maintained above 4 for 21.1 h (89.5%) with esomeprazole 40 mg twice daily compared 8 Esomeprazole 40 mg b.i.d. Pantoprazole 40 mg b.i.d. with 16.8 h (70.8%) with pantoprazole 40 mg twice daily during a 24-h monitoring period. Significant differences in favour of esomeprazole were found independent of the body position (percentage of time with ph > 4: upright 92.4 vs (P < ); supine 80.6 vs (P ¼ )). An intragastric ph > 4 for more than 16 h was achieved in 29 of 30 subjects with esomeprazole (96.7%) and in 17 of 30 volunteers (56.7%) with pantoprazole (P ¼ ) (Figure 2). During night-time the proportion of time with intragastric ph > 4 was 85.4% with esomeprazole and 63.6% with pantoprazole (P ¼ ). Nocturnal acid breakthrough, defined as intragastric ph < 4 for at least one consecutive hour between 10 pm and 6 am, was observed in eight subjects with esomeprazole (26.7%) and in 22 subjects with pantoprazole (73.3%) (P ¼ 0.009). The percentage of time that intragastric ph remained above ph 3.0, 3.5, 4.0, 4.5, and 6.0 was significantly higher with esomeprazole 40 mg twice daily compared with pantoprazole 40 mg twice daily, respectively (Figure 3). The mean differences (95% CI) increased with rising ph threshold: for ph 3, 13.6% ( ); ph 4, 18.7% ( ); ph 5, 24.4% ( ) and for ph 6, 29.1% ( ). Safety and tolerability Both esomeprazole and pantoprazole were well tolerated. Based on pill count on day 5 of each treatment period, all subjects complied to the protocol. No serious adverse events or premature discontinuations because of an adverse event occurred. Six and eight subjects reported minor adverse events during esomeprazole and Median ph A.m. P.m. A.m. Figure 1. Median intragastric ph throughout day 5 of treatment with esomeprazole 40 mg twice daily and pantoprazole 40 mg twice daily. Esomeprazole 40 mg b.i.d Pantoprazole 40 mg b.i.d. Figure 2. Proportion of subjects with intragastric ph > 4 for more than 16 h during a 24-h period on day 5 of treatment with esomeprazole 40 g twice daily and pantoprazole 40 mg twice daily (P ¼ ).

4 966 S. MIEHLKE et al. Percentage of time with ph above threshold pantoprazole treatment, respectively. Most commonly reported adverse events were headache, nausea, bloating and diarrhoea. There were no clinically meaningful changes in routine laboratory measurements. DISCUSSION * * ph threshold Esomeprazole 40 mg b.i.d. Pantoprazole 40 mg b.i.d. Figure 3. Mean percentage of time in which intragastric ph was maintained above ph thresholds on day 5 of treatment with esomeprazole 40 mg twice daily and pantoprazole 40 mg twice daily (*P < 0.001; P < compared with pantoprazole). The results of this crossover study demonstrated a significantly better control of intragastric acidity throughout the total 24-h period and the prespecified time windows with esomeprazole 40 mg twice daily compared with pantoprazole 40 mg twice daily. Even more importantly, almost all volunteers had intragastric ph values >4 for more than 16 h as compared with 17 of 30 subjects on pantoprazole. Nocturnal acid breakthrough did occur significantly less under esomeprazole compared with pantoprazole treatment. Our results expand recent crossover studies consistently showing a significantly higher degree of intragastric acid suppression provided by esomeprazole 40 mg daily compared with omeprazole 20 and 40 mg, lansoprazole 30 mg, pantoprazole 40 mg and rabeprazole 20 mg. 8 11, These studies have shown that at steady state esomeprazole 40 mg once daily provides an intragastric ph > 4 for about 15 h within a 24-h period. However, even with standard dose esomeprazole only about half of subjects achieved effective control of intragastric ph for >16 h. 20 This could be the reason for the consistent observation that about 10 20% of the patients with severe erosive oesophagitis do not heal after 8 weeks of esomeprazole treatment The results of our study corroborate previous findings of a recent double-blind crossover study in healthy subjects showing that esomeprazole at a dose of 20 mg twice daily and 40 mg twice daily provided a greater degree of intragastric acid suppression than esomeprazole 40 mg once daily. 21 With esomeprazole 40 mg twice daily, Katz et al. demonstrated a mean of 19.2 hours with an intragastric ph > 4 in a 24-h period, which is similar to our finding of a mean time of 21.1 h with ph > 4. In contrast to the study by Katz et al., we found a slightly higher percentage of time with intragastric ph > 4 in upright position compared with supine position, while the respective figures obtained for the supine position were similar in both studies. The reason for the small difference between the US study and our present study remain speculative but may include differences in the mean age of the study populations (37 vs. 25 years, respectively), the H. pylori status (20% seropositive for H. pylori in the US study) or in the ethnic background. In the study by Katz et al. 60% of subjects were African- American and another 12% represented other ethnicities. 21 Relevant differences in polymorphisms of the CYP2C19 genotype appear unlikely to explain the differences, as in the US study the majority (96%) of subjects had an extensive metabolizer status. In the present study, we did not investigate the CYP2C19 genotype of our subjects. However, a recent study of our group has shown that in our catchment area the majority of patients (98%) had a genotype encoding for an extensive metabolizer status which is likely to be representative for our population. 22 Both the study by Katz et al. and the present study suggest that esomeprazole 40 mg twice daily is currently the treatment option of choice if a predictable increase of the intragastric ph above 4 for more than 16 h, i.e. for the treatment of refractory erosive oesophagitis, complicated GERD or nocturnal acid breakthrough. However, clinical trials investigating the efficacy of twice-daily dosing of esomeprazole in such patients are lacking at this time. In conclusion, esomeprazole 40 mg twice daily provides significantly greater intragastric acid suppression than pantoprazole 40 mg twice daily. Twice-daily dosing of esomeprazole guarantees intragastric ph values above 4 for more than 16 h in almost all subjects taking the drug as prescribed. Clinical studies should now evaluate whether this pharmacodynamic superiority translates into clinical practice.

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