Oral esomeprazole vs. intravenous pantoprazole: a comparison of the effect on intragastric ph in healthy subjects

Transcription

1 Aliment Pharmacol Ther 2003; 18: doi: /j x Oral esomeprazole vs. intravenous pantoprazole: a comparison of the effect on intragastric in healthy subjects D. ARMSTRONG*, D. BAIR*, C. JAMES*, L. TANSER, S. ESCOBEDO & K. NEVIN *Division of Gastroenterology, McMaster University & Hamilton Health Sciences, Hamilton, ON, Canada; and AstraZeneca Canada Inc., Mississauga, ON, Canada Accepted for publication 10 July 2003 SUMMARY Background: Intravenous (IV) proton-pump inhibitor therapy is used in patients who cannot take oral medications or require greater acid suppression. Oral esomeprazole produces greater acid suppression than oral pantoprazole; however, no comparative data exist for oral esomeprazole and IV pantoprazole. Aim: To compare acid suppression (time with > 3.0, 4.0, 5.0 and 6.0) produced by standard doses of oral esomeprazole and IV pantoprazole in healthy subjects. Methods: A randomized, two-way crossover study in 30 subjects receiving oral esomeprazole (40 mg o.d.) or IV pantoprazole (40 mg o.d.) for 5 days followed by a 2-week washout period before the second 5-day drug administration period using the crossover drug regimen. Results: Oral esomeprazole produced greater acid suppression than IV pantoprazole on day 1 [ > 3.0 (56.9%, 35.8%; P < 0.001), > 4.0 (43.4%, 25.0%; P < 0.001) and > 5.0 (28.7%, 15.6%; P < 0.001)] and on day 5 [ > 3.0 (70.4%, 45.9%; P < 0.001), > 4.0 (59.2%, 33.9%; P < 0.001), > 5.0 (45.5%, 23.9%; P < 0.001) and > 6.0 (19.6%, 12.6%; P ¼ 0.045)]. The adverse event profiles indicated both treatments to be safe and well tolerated. Conclusions: In healthy subjects, esomeprazole, 40 mg o.d. dispersed in water, produces greater acid suppression than pantoprazole 40 mg IV o.d. after 1 and 5 days of medication. INTRODUCTION Oral proton-pump inhibitor therapy produces a high degree of acid suppression and is very effective for the management of acid-related disorders. High-dose, intravenous proton-pump inhibitor therapy given as a bolus followed by a continuous infusion is recommended for patients with upper gastrointestinal haemorrhage; intravenous proton-pump inhibitor therapy may also be required for patients who are unable to take oral medication. 1, 2 Currently, pantoprazole is the only IV Correspondence to: Dr D. Armstrong, Division of Gastroenterology, HSC- 4W8, McMaster University Medical Centre, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. armstro@mcmaster.ca proton-pump inhibitor commercially available in North America, and its use in the hospital environment has led to increasing concerns about appropriate use of IV acid suppressants and the potential for increased costs. 3, 4 With this in mind, oral proton-pump inhibitors might be prescribed more readily for hospital inpatients if it could be shown clearly that they are comparable to IV protonpump inhibitors., the S-isomer of omeprazole, has an improved pharmacokinetic profile leading to greater acid suppression than that produced by omeprazole, pantoprazole, lansoprazole and rabeprazole. 5 In clinical studies, the greater acid suppression produced by esomeprazole has translated into higher healing rates and more effective symptom relief when compared to lansoprazole and omeprazole in gastro-oesophageal Ó 2003 Blackwell Publishing Ltd 705

2 706 D. ARMSTRONG et al. reflux disease (GERD) patients. 6 8 A recent study showed no difference between the oral and IV formulations of pantoprazole (20 and 40 mg) with respect to reduction of gastric acid output in patients with GERD. 9 Furthermore, subjects who received 30 mg of lansoprazole (administered nasogastrically with apple sauce) demonstrated a higher 24-h intragastric and sustained more intragastric than when they received 40 mg of pantoprazole IV. 10 Thus, it can be postulated that oral esomeprazole will produce acid suppression greater than that produced by IV pantoprazole. Oral esomeprazole, which is available in many countries as a dispersible, multiple-unit, enteric-coated pellet formulation, can be used in patients with a nasogastric tube in situ. Stability data for the multiple unit pellet system (MUPS) tablet has shown the enteric-coated pellets to remain intact for up to 30 min when dispersed in water or in apple sauce and to be bioequivalent to the 11, 12 intact tablet. The purpose of this study was to compare the pharmacodynamics, and thereby the degree of acid suppression, produced by standard doses of oral esomeprazole and IV pantoprazole by comparing the median 24-h values and the percentages of the 24-h recording period during which intragastric was greater than 3, 4, 5 and 6 on days 1 and 5 of drug administration in healthy Helicobacter pylori negative subjects. The primary hypothesis of this study was that oral esomeprazole administered as an oral suspension produces greater acid suppression than IV pantoprazole, as indicated by the time during which intragastric is greater than 4.0 on day 1 of drug administration. MATERIALS AND METHODS Subjects Thirty healthy male and female subjects participated in a single-centre study at the McMaster University Medical Centre site of Hamilton Health Sciences. Subjects were enrolled if a prescreen assessment indicated a normal medical history, physical examination, electrocardiogram (ECG) and laboratory findings. Inclusion in the trial required written informed consent from the subject, a body mass index (BMI) between 19 and 27 kg/m 2 and weight between 50 and 100 kg. Absence of H. pylori infection was established by 13 C-urea breath test (UBT) (Isodiagnostika Inc., Edmonton, AB, Canada); breath samples were analysed at McMaster University Medical Centre by isotope ratio mass spectrometry according to standard protocols (Breath Mat, Finnigan Mat, Bremen, Germany). The major exclusion criteria were the presence of any upper gastrointestinal tract symptoms, any significant concurrent disease or clinical illness during 14 days prior to enrolment, a blood donation or the use of an investigational drug or device within 12 weeks prior to enrolment, the use of prescription drugs within 14 days prior to baseline recording, or the use of over-the-counter drugs within 7 days prior to the baseline visit; acetaminophen and oral contraceptives were permitted. Proton-pump inhibitors, prokinetic agents, antibiotics and bismuth-containing compounds were not allowed for 30 days prior to baseline recordings. Subjects with a history of past or current drug or alcohol abuse were ineligible, as were female subjects who were pregnant or lactating. Design This was a randomized, open-label, two-way crossover study. After an initial prescreen visit to determine eligibility and a 24-h baseline recording within 2 weeks of drug administration, subjects were randomized to initial therapy with either oral esomeprazole (40 mg o.d.), administered as an oral suspension or IV pantoprazole (40 mg o.d.) for five consecutive days. This was followed by a 2-week washout period before the second 5-day drug administration period using the crossover drug regimen. Subjects were instructed not to smoke or use alcohol at any time during the trial (Figure 1). Oesophageal manometry was performed during the prescreen visit to determine the location of the lower oesophageal sphincter (LOS). The electrode was passed transnasally into the stomach and positioned 10 cm below the manometrically defined LOS. Sequential gastric values were recorded every 4 s by the data recorder, and then downloaded to a native format Pre-screen Observation > 7 days Baseline (oral 40 mg od) (IV 40 mg od) (oral 40 mg od) (IV 40 mg od) Washout Period Day 1 5 > 14 days Day 1 5 Figure 1. Study flow chart.

3 GASTRIC WITH ORAL ESOMEPRAZOLE OR IV PANTOPRAZOLE 707 Medtronic data file before conversion to an ASCII file for analysis. Analysis of data was performed according to established techniques using dedicated software for summary and graphical presentation. 13 In all, five ambulatory recordings were performed using a single-channel, internally referenced glass electrode (Ingold M440, Medtronic) attached to a Digitrapper III data recorder (Medtronic, Mississauga, ON, Canada); one 24-h recording was performed on days 1 and 5 of drug administration after an initial, baseline pre-treatment recording. Subjects fasted from midnight until the start of the recording the following morning, and were then provided with one of two standard nutrition regimens based on body weight. Each regimen consisted of three meals and one snack for each day of recording. Breakfast was taken 1 h following probe placement, lunch was taken between 12:00 and 13:00, dinner between 18:00 and 19:00 and a light snack at 20:00. Routine clinical chemistry and haematology were performed at the prescreen visit and on day 5 of drug administration for evaluation of safety data (Core Laboratory, Hamilton Health Sciences, Hamilton, ON, Canada). A serum human chorionic gonadotropin (hcg) test was performed for all female subjects at the prescreen visit, day 1 of the second drug administration period and on the final visit. A follow-up telephone contact was arranged 2 weeks following the last visit (the fifth day of drug administration during the second crossover treatment period) to monitor subjects for ongoing adverse events. Study drug MUPS tablets (rapid dispersible formulation; AstraZeneca R & D, Mölndal, Sweden) 40 mg, were taken orally once each morning on the days of drug administration. Tablets were dispersed in 100 ml of noncarbonated, room-temperature water and stirred for approximately 2 min, until the tablet had dispersed completely; stability data indicate that the entericcoated pellets of esomeprazole remain intact for up to 30 min after dispersal in water. 11 The solution was drunk within 15 min of dispersal and the glass was rinsed with 100 ml of water, which was drunk immediately to ensure ingestion of any tablet residue. IV solutions were also administered once daily in the morning. The solution was prepared by injecting 10 ml of 0.9% NaCl into the vial containing the dry lyophilized powder (pantoprazole 40 mg; pantoprazole sodium 42.3 mg; Altana Pharma, Constanz, Germany). The reconstituted solution, diluted with 90 ml of 0.9% NaCl injection, was infused over 15 min and used within 6 h of preparation. Statistics The number of subjects was calculated to demonstrate that oral esomeprazole (40 mg o.d.) is more effective in controlling intragastric, to IV pantoprazole (40 mg o.d.) by at least 6% with respect to the percentage of time during which was greater than 4.0 on day 1. Assuming a within-subject standard deviation of 11%, detection of a difference of this magnitude, with a power of 0.8 and a type I error of 0.05, required 26 subjects. Assuming a dropout rate of 20% (including protocol violators, technical failures and withdrawals), 30 volunteers were included. For each 24-h recording period the median 24-h was calculated. Statistical analysis used parametric tests and presented the data as the mean of the median 24-h values. A mixed analysis of variance (anova) was carried out for the percentage of time that gastric was greater than 3.0, 4.0, 5.0 and 6.0, with the mean of the 24-h median as the dependent variable, the sequence, period and treatment as fixed effect factors, and the subject as a random effect factor. Confidence intervals and P-values were used to assess the treatment effects within and between treatments. Ninety-five percent confidence interval estimates of the individual true mean effects, least-square means (LSM) of percentage time > 3.0, 4.0, 5.0 and 6.0 were calculated. The percentages of subjects having a greater than 3.0, 4.0, 5.0 and 6.0 for the first 4 h of each recording were also calculated and compared between treatments for day 1 using the v 2 -test. Likewise, the number of subjects that maintained their greater than 4.0 during 12 and 16 h after drug administration during both days 1 and 5 were compared between esomeprazole and pantoprazole using McNemar s test. A spline interpolation was used to smooth the individual data for the 24-h data plot. RESULTS Thirty subjects were randomized and received at least one dose of study medication. Two subjects were

4 708 D. ARMSTRONG et al. excluded from selected analyses due to technical failures leading to the loss of and other data; one subject had incomplete data and the other had incomplete demographic data, pk data and data due to technical failure. Demographics for the 29 subjects with complete data (20 males; 9 females) showed a mean (s.d.) age of 25.3 (5.9) years, weight 77.5 (10.5) kg, height (9.3) cm and BMI 25.1 (1.9) kg/m 2. Oral esomeprazole produced a significantly greater percentage of time during which was greater than 4.0 compared to pantoprazole IV on day 1 of drug administration (43.4, 25.0; P < 0.001). Similarly, on day 1 of drug administration, oral esomeprazole produced a significantly greater percentage of time with greater than 3.0 (56.9, 35.8) and 5.0 (28.7, 15.6) (P < 0.001) compared with IV pantoprazole. There were no significant differences between the two treatments with respect to the percentage of time with > 6.0 on day 1 (10.5, 7.5; P ¼ 0.27). Similar results were observed on day 5; oral esomeprazole produced a significantly greater percentage of time with greater than 3.0 (70.4, 45.9), 4.0 (59.2, 33.9), 5.0 (45.5, 23.9) (P < for all) and 6.0 (19.6, 12.6; P ¼ 0.045) compared with IV pantoprazole (Figure 2). Oral esomeprazole produced a greater increase in intragastric on day 1 that was evident throughout the 24-h recording periods, compared with IV pantoprazole (Figure 3). At baseline the group mean value % 24-hr recording > 3.0 * P < 0.05 P < > 4.0 > 5.0 > 6.0 threshold day 1 day 1 day 5 day 5 * Figure 2. Mean percentages of the 24-h recording period (95% CI) on day 1 (first 2 bars) and day 5 (last 2 bars) during which intragastric exceeded thresholds of 3.0, 4.0, 5.0 and 6.0 for esomeprazole (dark bars) and pantoprazole (light bars). Day 1 Median B L D Sn Figure 3. Median 24-h intragastric curves (n ¼ 28) for day 1 showing the baseline curve (before therapy) as a reference for each graph (solid line, esomeprazole; dashed line, pantoprazole). Arrows indicate the timing of the standard meals (B, breakfast; L, lunch; D, dinner; Sn, snack).

5 GASTRIC WITH ORAL ESOMEPRAZOLE OR IV PANTOPRAZOLE 709 [95% confidence interval (CI)] for the median 24-h was 1.75 ( ), and on day 1 oral esomeprazole [mean 3.6 ( )] produced a higher median 24-h than IV pantoprazole [2.5 ( ); P < 0.001]. This difference was maintained (Figure 4) at day 5 [oral esomeprazole: 4.6 ( ) compared with IV pantoprazole: 2.9 ( ); P < 0.001]. Intragastric was greater than 4.0 for 12 or more hours in 35.7% and 3.6% of esomeprazole and pantoprazole subjects, respectively, on day 1 (P ¼ 0.002) and 85.7% and 7.1%, respectively, on day 5 (P < ). maintained gastric > 4.0 for greater than 16 h in 7.1% of patients compared with 3.6% for pantoprazole on day 1 (P > 0.05), and in 32.1% of patients compared with 3.6% pantoprazole on day 5 (P ¼ 0.005) (Figure 5). Intragastric during the first 4 h of the recording on day 1 was greater than 5.0 (esomeprazole, 96.4%; pantoprazole, 64.3%; P < 0.01) and 6.0 (esomeprazole, 60.7%; pantoprazole, 25%; P < 0.05) in a greater proportion of subjects after oral esomeprazole than after IV pantoprazole; a similar trend was seen for greater than 3.0 (esomeprazole, 100%; pantoprazole, 96.4%; P > 0.05) and 4.0 (esomeprazole, 96.4%; pantoprazole, 85.7%; P > 0.05) (Figure 6). Analysis of pharmacokinetic data indicates that both study drugs achieved adequate drug levels indicative of subject compliance with the administration schedules. There were no significant differences in the incidence of adverse events between the two treatments. The most commonly reported adverse events for both treatments were headache, sore throat, bloating and diarrhoea. Both drugs were safe and well tolerated in all subjects. DISCUSSION The results of the present study are consistent with the results of previous comparative studies. As oral esomeprazole (40 mg o.d.) produces a greater reduction in gastric acidity than oral pantoprazole (40 mg o.d.), 14 it had been hypothesized that oral esomeprazole (40 mg o.d.) would produce a greater increase in Day 5 Median Figure 4. Median 24-h intragastric curves (n ¼ 28) for day 5 showing the baseline curve (before therapy) as a reference for each graph (solid line, esomeprazole; dashed line, pantoprazole). Arrows indicate the timing of the standard meals (B, breakfast; L, lunch; D, dinner; Sn, snack). B L D Sn Day 1 Day 5 12 hours 16 hours 12 hours 16 hours 35.7% 7.1% 85.7% 32.1% Figure 5. Percentage of subjects who had an intragastric greater than 4.0 for 12 and 16 h (or more) per day during treatment on days 1 and 5 with esomeprazole and pantoprazole. 3.6% 3.6% 7.1% 3.6%

6 710 D. ARMSTRONG et al. Percentage of Subjects N.S. N.S. >3.0 >4.0 >5.0 >6.0 threshold P < 0.01 P < 0.05 Figure 6. Mean percentages of the initial 4-h segment of the recording period (95% CI) on day 1 during which intragastric exceeded thresholds of 3.0, 4.0, 5.0 and 6.0 for esomeprazole (white columns) and pantoprazole (grey columns). gastric than intravenous pantoprazole (40 mg o.d.). This hypothesis was confirmed unequivocally, and although the degree of acid suppression produced by both proton-pump inhibitors increased from day 1 to day 5 of administration, the difference between the two proton-pump inhibitors was, if anything, greater at day 5. Furthermore, oral esomeprazole produced a greater increase in during the first 4 h after drug administration on day 1, indicating that IV administration does not necessarily produce a faster onset of action. For patients with acid-related disorders such as erosive oesophagitis and peptic ulcer disease, lesion healing and symptom relief are related directly to the degree of acid suppression achieved by medical therapy Protonpump inhibitors are the most effective acid-suppressing agents currently available and, in the vast majority of patients, oral proton-pump inhibitors are highly effective therapeutic agents for most acid-related disorders. Indeed, the indications for intravenous or enteral proton-pump inhibitor administration are quite limited; patients requiring proton-pump inhibitors who cannot take anything by mouth should receive their medication intravenously. However, it is not uncommon for IV proton-pump inhibitors to be used for patients who are unable to swallow, even if there is a nasogastric tube in situ. This may be due, in part, to a perception that an oral proton-pump inhibitor is less effective than an intravenous formulation and, in part, to concerns that oral proton-pump inhibitors cannot be administered easily via a nasogastric tube. Oral esomeprazole, the S-isomer of omeprazole, has higher bioavailability than either the R-isomer or racemic omeprazole, and it produces a greater degree of acid suppression at a standard, once-daily dose, with a higher median 24-h, and a greater proportion of the 24-h recording period during which gastric exceeds More recently, it has been reported that oral and intravenous pantoprazole are also equivalent, even when administered at a high dose ( mg daily) in healthy volunteers, comparable to doses used for the management of upper gastrointestinal tract haemorrhage (80 mg bolus, followed by an infusion of 19, 20 8 mg/ h). This study was conducted in healthy subjects, and the results should therefore be extrapolated with caution to patients in an intensive care unit (ICU) and those who are being treated for upper gastrointestinal bleeding. The baseline data indicate that all subjects had normal gastric secretory function, unlike some ICU patients in whom gastric acid secretion may be compromised by severe concomitant illness. The route of administration is also important, particularly for ICU patients. Patients being treated for upper gastrointestinal haemorrhage may be able to take oral medication, but many ICU patients can take medications only intravenously or via a nasogastric tube. In the present study, esomeprazole was not administered nasogastrically; however, given that the total volume of the suspension is only slightly larger than that which can be given nasogastrically, and given that the dispersed MUPS tablet is bioequivalent to the intact tablet, it is unlikely that the administration of an oral suspension altered the observed intragastric significantly. 8 Subjects in this study were not fasted, and the effect of food ingestion on gastric is evident in the mean curves, with rises occurring at 3, 6 and 12 h after the start of the recordings (Figures 3 and 4). However, subjects took the same standardized meals throughout all recording periods, so the observed difference between the two medications is very unlikely to have been mealrelated. Although the present study was conducted in healthy subjects, there is no indication from previous studies that differences between proton-pump inhibitors are limited to a specific subset of individuals. The effect of oral esomeprazole, compared with intravenous proton-pump inhibitors, should now be tested in ICU patients able to take proton-pump inhibitors by mouth or nasogastric tube. In addition, these data may also provide a basis for an appropriate transition from intravenous to oral proton-pump inhibitor therapy for hospital inpatients; this has important cost implications because there are now increasing data to indicate that

7 GASTRIC WITH ORAL ESOMEPRAZOLE OR IV PANTOPRAZOLE 711 much of the current inappropriate use of intravenous proton-pump inhibitors is due to a delayed transition to oral medication rather because of an inappropriate institution of intravenous therapy. 3, 4, 21 The results of this study demonstrated that oral esomeprazole dispersed in water produced greater intragastric acid suppression than IV pantoprazole in equal doses (40 mg o.d.). It is also possible, at higher doses than those used in the current study, that oral therapy with esomeprazole may produce greater acid suppression, at equivalent doses, than IV pantoprazole. ACKNOWLEDGEMENTS Supported by an unrestricted grant from AstraZeneca Canada Inc, Mississauga, ON, Canada. REFERENCES 1 Lau JY, Sung JJ, Lee KK, et al. Effect of intravenous omeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers. N Engl J Med 2000; 343: British Society of Gastroenterology Endoscopy Committee. Non-variceal gastrointestinal haemorrhage: guidelines. Gut 2002; 51(suppl 4): iv Bair FD, Armstrong D, Zhou P. Intravenous acid suppression appropriateness of use in a tertiary care setting. Gastroenterology 2001; 120: A730 (Abstract). 4 Zadieh I, Andrews C, Brodie M, et al. Prescribing practices and indications for the use of intravenous proton pump inhibitors (IV PPI) in an urban tertiary care centre. Can J Gastroenterol 2002; 16: Spencer CM, Faulds D.. Drugs 2000; 60: Kahrilas PJ, Falk GW, Johnson DA, et al. improves healing and symptom resolution as compared with omeprazole in reflux esophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther 2000; 14: Castell DO, Kahrilas PJ, Richter JE, et al. (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002; 97: Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001; 96: Metz DC, Pratha V, Martin P, et al. Oral and intravenous dosage forms of pantoprazole are equivalent in their ability to suppress gastric acid secretion in patients with gastroesophageal reflux disease. Am J Gastroenterol 2000; 95: Freston J, Chiu Y, Pan W, et al. Effects on 24-hour intragastric : a comparison of lansoprazole administered nasogastrically in apple juice and pantoprazole administered intravenously. Am J Gastroenterol 2001; 96: Röhss K, Hassan-Alin M, et al. Bioequivalence of esomeprazole 40mg tablet dispersed in water and the intact tablet in male and female healthy volunteers. Gut 2002; S2: A168 (Abstract). 12 Andersson T, Magner D, et al. 40 mg capsules are bioequivalent when administered intact or as the contents mixed with applesauce. Clin Drug Invest 2001; 21: Armstrong D, Emde D, et al. Long-term ambulatory gastric -metry: easy to do but difficult to analyze. Eur J Gastroenter Hepatol 1991; 1: Wilder-Smith C, Röhss K, Rydholm H, et al. 40 mg provides more effective acid control than pantoprazole 40 mg. Gastroenterology 2000; 118: A20 (Abstract). 15 Jones DB, Howden CW, Burget DW, et al. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987; 28: Howden CW, Hunt RH. The relationship between suppression of acidity and gastric ulcer healing rates. Aliment Pharmacol Ther 1990; 4: Burget DW, Chiverton SG, Hunt RH. Is there an optimal degree of acid suppression for healing of duodenal ulcers? Gastroenterology 1990; 99: Bell NJ, Burget D, Howden CW, et al. Appropriate acid suppression for the management of gastroesophageal reflux disease. Digestion 1992; 51: Lind T, Rydberg L, Kyleback A, et al. provides improved acid control vs. omeprazole in patients with symptoms of gastroesophageal reflux disease. Aliment Pharmacol Ther 2000; 14: Bair FD, James C, Armstrong D. Maximal acid suppression: oral vs. intravenous pantoprazole. Gastroenterology 2002; 122: A Kaplan GG, Bates D, McDonald D, et al. Inappropriate use of intravenous proton pump inhibitors: Problem extent and cost implications. Am J Gastroenterol 2002; 97: S236.