To compare antisecretory effects of rabeprazole and esomeprazole after single and repeat dosing in Helicobacter pylori-negative healthy volunteers.
Results were pooled from three smaller, open, crossover, randomized studies to obtain data from 80 subjects. The studies compared: (a) 5 days’ dosing of 20 mg rabeprazole and esomeprazole (n = 24); (b) single doses of rabeprazole 20 mg and esomeprazole 40 mg (n = 27) and (c) 5 days’ dosing of rabeprazole 10 mg and esomeprazole 20 mg (n = 29). Washout periods were ≥14 days. Intragastric pH was recorded continuously for 24 h on days 0, 1 and 5.
Single doses of rabeprazole 20 mg maintained 24-h intragastric pH >4 for longer than esomeprazole 20 mg (45% vs. 32%; P < 0.001); rabeprazole 20 mg and esomeprazole 40 mg were equivalent in their effects. After 5 days’ dosing, rabeprazole 20 mg maintained pH >4 for longer than esomeprazole 20 mg (62% vs. 56%; P = 0.046); the reverse was true for esomeprazole 20 mg vs. rabeprazole 10 mg (56% vs. 48%; P = 0.035). In general, intragastric pH AUC during 0–5 h after dosing was higher after esomeprazole than rabeprazole, whereas the reverse was true during the night.
The order of effects on 24-h pH was: rabeprazole 10 mg ≤ esomeprazole 20 mg < rabeprazole 20 mg = esomeprazole 40 mg. Esomeprazole acts faster, whereas rabeprazole's effect lasts longer.
Proton pump inhibitors (PPIs) suppress acid secretion by blocking the gastric acid pump, H+, K+-ATPase, and are widely used for the treatment of acid-related disorders, including gastro-oesophageal reflux disease (GERD). All PPIs are powerful inhibitors of gastric acid secretion, and are generally regarded as superior to histamine H2-receptor antagonists in symptom relief and healing rates.1 However, there are pharmacological differences among the PPIs that may have implications for their clinical efficacy. For example, rabeprazole, lansoprazole and pantoprazole exhibit linear pharmacokinetics and reach their full bioavailability after a single dose, whilst the bioavailability of omeprazole and esomeprazole increases after repeat dosing.2, 3
Head-to-head comparisons of the efficacy of PPIs are lengthy, and require very many patients if they are to distinguish among treatments that differ only slightly in therapeutic effects. In contrast, clinical pharmacology studies of PPIs in small numbers of healthy volunteers allow the comparison of the potency, and time course, of their effects on intragastric pH. Intragastric pH, particularly percentage time pH >4, is an established biomarker of the therapeutic efficacy of antisecretory agents.4, 5 Maintenance of pH >4 is an important objective in management of GERD: when the pH of the acid refluxate falls below 4, patients experience mucosal injury in the oesophagus.4, 6 Therefore, we aimed to compare the potency and time course of the antisecretory effects of rabeprazole and esomeprazole in healthy volunteers, to allow the prediction of efficacy of different doses, and dosing regimes, of those two PPIs.
We combined the results of three open-label, randomized, two-way crossover studies of PPIs in healthy, Helicobacter pylori-negative volunteers. The studies compared rabeprazole 20 mg vs. esomeprazole 20 mg; rabeprazole 10 mg vs. esomeprazole 20 mg and rabeprazole 20 mg vs. esomeprazole 40 mg. Combining the results from the three studies allowed us to compare more dosing regimens than would be possible in a single study, and is justified, because of the uniformity of the volunteer population, and of the study methods. The three studies were done according to nearly identical protocols, at the same research unit, by the same investigator and study team, using identical pH recorders and the same outcome measures.
Subjects and methods
Subjects were healthy, non-smoking men and women aged 18–45 years, with a body mass index (BMI) of 18.0–30.9 kg/m2, who volunteered to take part in one of three studies at the same research unit (Hammersmith Medicines Research). All were negative for H. pylori by serology and 13C-urea breath test [Pylobactell kit, Bureau of Stable Isotope Analysis (BSIA) Ltd, Middlesex, UK; samples analysed by BSIA with European Scientific Tracermass Isotope Ratio Mass Spectrometer and RoboPrep G Automatic Breath Sampler]. None of the subjects had a history of: dyspepsia; gastrointestinal disorder affecting drug absorption or drug or alcohol abuse. They used no prescription medication (except oral contraceptives) in 4 weeks before the study, nor over-the-counter medication within 7 days of its start.
Each of the three studies was approved by the Brent Medical Ethics Committee, the local independent ethical review board. All subjects gave written informed consent.
Our analysis combines the results of three open-label, randomized, two-way crossover studies of rabeprazole and esomeprazole (Table 1). Two studies were repeat-dose studies; subjects received daily doses of rabeprazole and esomeprazole for 5 days. In the third study, subjects received a single dose of rabeprazole and esomeprazole. In each of the three studies, subjects participated in two study periods, separated by a washout period of at least 14 days. In all studies, the order of treatment with rabeprazole or esomeprazole was randomized using a sas program (sas for Windows, version 6.12).
|Number of subjects||Days of dosing||Dose of rabeprazole (mg)||Dose of esomeprazole (mg)||Males/females (n)||Age (years; mean, range)||BMI (kg/m2; mean, range)||Date study done|
|24||5||20||20||14/10||26.5 (20–43)||23.1 (19.4–30.8)||September to November 2000|
|29||5||10||20||15/14||25.6 (19–38)||23.8 (18.9–30.3)||March to May 2001|
|27||1||20||40||12/15||26.4 (19–43)||24.2 (19.1–28.4)||May to July 2001|
During each study period, subjects were resident at our clinical pharmacology unit in Central Middlesex Hospital from the evening before day 0 until 24 h after the final (or only) dose. After an overnight fast, we gave subjects either rabeprazole or esomeprazole with 100 mL of water, in the mornings of each dosing day. We measured intragastric pH from predose until 24 h after dosing on day 1, and at the corresponding times on day 0. In addition, in the repeat-dose studies, we measured intragastric pH at the corresponding times relative to dosing on day 5. On the days when we measured intragastric pH, subjects had standard meals and drinks at 1, 4 and 10 h after dosing. Alcohol, caffeinated beverages, smoking and strenuous exercise were not allowed during the interval from 48 h before day 0 until the end of each study period. Subjects returned 5–10 days after the last dose of study medication for a follow-up medical examination.
Measurement of intragastric pH
We recorded intragastric pH continuously on days 0 and 1, and, in the repeat-dose studies, on day 5. On day 0, after anaesthetizing the subject's nostril with lidocaine hydrochloride 1% spray (Xylocaine, Astra Zeneca, Wilmington, DE, USA), we inserted a disposable antimony internal reference pH electrode with surface markings of 1 cm (Zinetics Medical, Salt Lake City, UT, USA). We monitored pH during passage of the electrode down the oesophagus, through the gastro-oesophageal sphincter and into the stomach. We confirmed entry of the electrode into the stomach by a sharp fall in pH, usually to <3.2. We withdrew the electrode slowly to about 40 cm; a sharp rise in pH identified the point at which the electrode crossed the sphincter. We then advanced the electrode to a final position of 8–10 cm (depending on the subject's height) beyond the point at which the pH fell below 3. The electrode was positioned 54–62 cm from the nostril. We recorded intragastric pH every 6 s using a Flexilog 2020 96-h recorder (Oakfield Instruments, Oxford, UK), which had been precalibrated, using buffers at pH 4 and 7, before passage of the electrode. We uploaded the recorded data to a PC, and analysed it using the flexisoft ii software (Oakfield Instruments), running under Windows NT.
We removed the pH electrode on the morning of day 2, after 48 h of recording. In the repeat-dose studies, about 1 h before dosing on day 5, we inserted a new pH electrode, and recorded pH for at least 24 h after dosing.
Data were analysed using sas for Windows, version 6.12; the null hypothesis was rejected if P-values were 0.05 or less. The primary analysis was carried out on the ‘per-protocol’ population, which included all randomized subjects who completed a full course of each treatment, had no appreciable loss of pH data, and had no major protocol violations.
The area under the intragastric pH vs. time curve (AUC) was calculated over the intervals of 0–24 h, and 0–5, 5–11, 11–14 and 14–24 h on days 0, 1 and 5, using the linear trapezoidal method. Percentage of time that intragastric pH was >3 and >4 was calculated over the intervals of 0–14, 14–24 and 0–24 h. To stabilize the variance and make the data conform to a normal distribution, AUCs were log-transformed and percentages were arcsin-transformed.
To test for differences between treatments in intragastric pH, we did a linear mixed effect analysis on AUC data, and percentage time pH >3 and >4, using sas proc mixed. A separate analysis was caried out for days 1 and 5. All models contained fixed effects for period, study, sequence (i.e. treatment order) and treatment, and random effects for subject nested within sequence. In addition, day 0 AUC, or percentage time pH >3 and >4, was included in the model as a covariate. If the treatment effect was statistically significant in the overall model, paired comparisons between each dosage of rabeprazole and esomeprazole were underwent. No adjustments were made for multiple comparisons. Comparisons between the two dosages of rabeprazole, or between the two dosages of esomeprazole, were not carried out.
We pooled results from three smaller, open, randomized crossover studies of rabeprazole and esomeprazole at various doses to obtain intragastric pH data from 80 subjects, 41 (51%) men and 39 (49%) women. Their mean age was 26.2 years (range: 19–43), weight 71.6 kg (range: 49.6–103.6), height 173.1 cm (range: 149–195) and BMI 23.8 kg/m2 (range: 18.9–30.8). Seventy-five (94%) subjects were Europid, three (4%) were Afro-Caribbean and two (2%) were Indian/Asian. All subjects included in the analysis had pH data that was ≥93% complete. A summary of the individual studies is shown in Table 1.
Twenty-nine subjects received five doses of rabeprazole 10 mg, 24 subjects received five doses of rabeprazole 20 mg and 27 subjects received a single dose of rabeprazole 20 mg. Fifty-three subjects received five doses of esomeprazole 20 mg, and 27 subjects received a single dose of esomeprazole 40 mg.
There was no significant difference in mean age, weight, height or BMI among subjects in the three studies (P ≥ 0.35, by anova). In addition, there was a similar number of men and women, and non-Europid subjects, in each study.
Plots of median intragastric pH over 24 h on days 0, 1 and 5 are illustrated in Figure 1a–c; meal times are also indicated. Mean values and 95% confidence intervals (CI) of the pharmacodynamic variables are shown in Tables 2 and 3; differences that are statistically significant are indicated.
|Day||pH||Interval (h)||RAB 10 mg||RAB 20 mg||ESO 20 mg||ESO 40 mg||*|
|1||>3||0–14||52.7 (44.3–61.1)||66.2 (60.9–71.6)||55.1 (48.6–61.6)||76.2 (70.0–82.4)||1|
|14–24||28.3 (21.2–35.4)||41.8 (35.0–48.6)||21.7 (16.9–26.6)||25.1 (18.0–32.2)||2|
|0–24||42.5 (35.4–49.7)||56.1 (51.2–60.9)||41.2 (36.1–46.3)||54.9 (48.9–60.9)||3|
|>4||0–14||39.8 (31.5–48.0)||54.7 (49.1–60.4)||43.4 (36.5–50.3)||65.4 (56.9–73.9)||4|
|14–24||18.5 (13.2–23.7)||32.1 (25.6–38.7)||15.5 (11.0–19.9)||17.0 (11.2–22.9)||5|
|0–24||30.9 (24.6–37.2)||45.3 (40.5–50.2)||31.8 (26.7–36.8)||45.2 (38.5–52.0)||6|
|5||>3||0–14||75.5 (70.0–81.0)||83.5 (79.2–87.8)||84.0 (80.7–87.2)||N/A||7|
|14–24||37.4 (29.3–45.6)||56.3 (47.4–65.3)||39.3 (33.0–45.5)||N/A||8|
|0–24||59.6 (54.2–65.0)||72.2 (66.7–77.6)||65.3 (61.5–69.2)||N/A||9|
|>4||0–14||62.2 (54.7–69.7)||75.9 (70.5–81.4)||75.4 (71.4–79.5)||N/A||10|
|14–24||28.0 (20.1–36.0)||43.2 (35.1–51.3)||28.4 (22.6–34.2)||N/A||11|
|0–24||48.0 (41.5–54.4)||62.3 (56.8–67.7)||55.8 (51.7–59.9)||N/A||12|
|Day||Interval (h)||RAB 10 mg||RAB 20 mg||ESO 20 mg||ESO 40 mg||*|
|1||0–5||53 186 (47 677–58 695)||57 252 (53 639–60 864)||60 363 (56 258–64 468)||73 962 (67 937–79 987)||1|
|5–11||71 420 (63 496–79 344)||88 781 (83 060–94 501)||73 445 (67 503–79 387)||91 566 (85 417–97 714)||2|
|11–14||46 976 (42 780–51 173)||54 181 (51 257–57 104)||45 754 (42 252–49 255)||51 503 (47 665–55 341)||3|
|14–24||93 398 (84 163–102 632)||114 080 (103 534–124 626)||89 259 (81 974–96 544)||91 135 (80 990–101 280)||4|
|0–24||264 980 (243 118–286 841)||314 293 (297 964–330 622)||268 821 (252 231–285 412)||308 166 (286 559–329 772)||5|
|5||0–5||73 394 (66 370–80 419)||78 856 (71 381–86 331)||86 178 (82 279–90 077)||N/A||6|
|5–11||92 744 (85 089–100 398)||108 485 (103 242–113 727)||99 609 (96 028–103 190)||N/A||7|
|11–14||54 415 (50 196–58 634)||61 916 (58 160–65 672)||57 978 (54 965–60 991)||N/A||–|
|14–24||111 820 (98 645–124 995)||139 199 (126 173–152 224)||111 570 (102 840–120 299)||N/A||8|
|0–24||332 373 (306 785–357 962)||388 456 (367 920–408 992)||355 335 (340 822–369 848)||N/A||9|
The effect of study period and sequence (the order in which the subject had rabeprazole and esomeprazole) on intragastric pH AUC and percentage of time with pH >3 and >4 was not statistically significant in any of the analyses, indicating that carryover of treatment effects from the first period to the second was negligible. The overall effect of treatment on AUC and percentage time pH >3 and >4 was statistically significant, on both days 1 and 5; hence pairwise comparisons between esomeprazole and rabeprazole at each dose level were carried out.
Effect of treatment on percentage time pH >3 and >4
On day 1, mean percentage time pH >3 and >4 was significantly higher after rabeprazole 20 mg than esomeprazole 20 mg in the 0–24 h as a whole, and during the day (0–14 h) and night (14–24 h; P ≤ 0.004; Table 2). Over 24 h, mean percentage time pH >3 and >4 did not differ significantly between esomeprazole 40 mg and rabeprazole 20 mg; however, during the day, it was higher after esomeprazole 40 mg, and during the night it was higher after rabeprazole 20 mg (P ≤ 0.006).
On day 1, mean percentage time pH >3 and >4 over 24 h, and during the day, was higher after esomeprazole 40 mg than rabeprazole 10 mg (P ≤ 0.019), although there was no difference between the two drugs at night. Mean percentage time pH >3 and >4 did not differ significantly between esomeprazole 20 mg and rabeprazole 10 mg, in any time interval.
After 5 days’ dosing, mean percentage time pH >3 and >4 was significantly higher after rabeprazole 20 mg than esomeprazole 20 mg in the 0–24 h as a whole, and at night (P ≤ 0.046). However, there was no difference between the two drugs during the day.
On day 5, mean percentage time pH >3 and >4 was significantly higher after esomeprazole 20 mg than rabeprazole 10 mg during the day (P ≤ 0.003), but there was no difference between the two drugs at night.
Effect of treatment on intragastric pH AUC
On day 1, mean intragastric pH AUC was significantly higher after rabeprazole 20 mg than esomeprazole 20 mg in the 0–24 h as a whole (P = 0.0001), and during all time intervals except 0–5 h, when there was no difference between treatments (Table 3). In the first 5 h after dosing, mean AUC was higher after esomeprazole 40 mg than rabeprazole 20 mg (P = 0.0001); the reverse was true during the night (14–24 h; P = 0.0001), and over 24 h, there was no difference between the two drugs.
On day 1, mean AUC over 24 h, and during the day (0–5 and 5–11 h), was higher after esomeprazole 40 mg than rabeprazole 10 mg (P ≤ 0.020), although there was no difference between the two drugs at night (11–14 and 14–24 h). Mean AUC did not differ significantly between esomeprazole 20 mg and rabeprazole 10 mg, in any time interval.
On day 5, mean AUC was significantly higher after rabeprazole 20 mg than esomeprazole 20 mg in the 0–24 h as a whole, and at night (14–24 h; P ≤ 0.006). However, in the first 5 h after dosing, mean AUC was higher after esomeprazole 20 mg than rabeprazole 20 mg (P = 0.003).
On day 5, mean AUC was significantly higher after esomeprazole 20 mg than rabeprazole 10 mg during the day (0–5 and 5–11 h; P ≤ 0.007), but there was no difference between the two drugs in the 0–24 h as a whole, or at night (11–14 and 14–24 h).
Safety and tolerability
In all three studies, both drugs were safe and well tolerated. Consistent with clinical experience, the most common events after both rabeprazole and esomeprazole were gastrointestinal disturbances, including nausea, diarrhoea, constipation and abdominal discomfort. Overall, subjects coped well with the discomfort of the pH electrode, with the other study procedures and with residence in the research ward.
Our combined results show that, over the 0–24-h interval after single doses, rabeprazole is more pharmacologically potent than esomeprazole, as shown by a consistently higher 24-h pH when the two PPIs were given at the same dose, and an equivalent 24-h pH when rabeprazole was given at half the dose of esomeprazole. After 5 days’ dosing, rabeprazole was still more potent than esomeprazole, as judged by rabeprazole's greater effect on 24-h pH, when the two PPIs were given at 20 mg daily. However, the effect of the PPIs on 24-h pH conceals notable differences in their time courses. Esomeprazole had a faster onset of action than did rabeprazole, as shown by higher daytime pH, particularly in the first 5 h after dosing. In contrast, rabeprazole had a more prolonged effect, as shown by higher intragastric pH during the night.
Although pH AUC and time pH >3 and >4 would be expected to be highly correlated, it is nevertheless reassuring that our results based on AUC are concordant with those based on pH holding time. It is also reassuring that the comparisons between rabeprazole 10 mg and esomeprazole 20 mg, and rabeprazole 20 mg and esomeprazole 40 mg, yield similar conclusions: in both cases, over a 24-h period, rabeprazole is about twice as potent as esomeprazole on a mg for mg basis, particularly when given as a single dose. Thus, the results of two of our three component studies are consistent with each other, and suggest that the doses we tested are on the steep part of the dose–response curve for both esomeprazole and rabeprazole.
We found a difference in the time course of the effects of rabeprazole and esomeprazole on intragastric pH, as illustrated in Figure 1: after single and repeat doses, the effect of esomeprazole was of faster onset, whereas the effect of rabeprazole was more prolonged. Intragastric pH was higher during the first 5 h after a single dose of esomeprazole 40 mg than after rabeprazole 20 mg, whereas during the night pH was higher after rabeprazole 20 mg than esomeprazole 40 mg. Furthermore, daytime pH was higher after single-dose esomeprazole 40 mg than rabeprazole 10 mg, but there was no difference at night. With repeat dosing, in the first 5 h after dosing, esomeprazole 20 mg increased pH more than did rabeprazole 20 mg, but night-time pH was higher after rabeprazole 20 mg. Others have reported similar differences in the timing of the effects of two drugs. In patients with GERD, percentage time pH >4 was higher in the first 6 h after a single dose of esomeprazole 20 mg than rabeprazole 20 mg, although there was no difference between the two PPIs over 24 h.7
Interestingly, Inamori et al. found that, in the first 6 h after single doses, rabeprazole 20 mg increased intragastric pH more than did omeprazole 20 mg.8 That finding was in healthy volunteers who were rapid CYP2C19 metabolizers. Both esomeprazole and omeprazole are metabolized through cytochrome P450 enzymes, whereas rabeprazole is metabolized partly via a non-enzymatic pathway. From our previous experience in similar volunteer populations, 95% of our subjects were likely to be rapid metabolizers. Esomeprazole is metabolized more slowly than omeprazole, which might account for the difference in response.
Although continuous maintenance therapy with a PPI may be needed in patients with erosive or ulcerative GERD,9, 10 intermittent or on-demand use can control symptoms adequately in patients with non-erosive GERD.11–13 On-demand therapy with a PPI requires an agent that acts rapidly and has a sustained onset of action after a single dose. Therefore, our finding of a difference between esomeprazole and rabeprazole in the time course of their effects after single doses may be particularly relevant to ‘on-demand’ or intermittent therapy. If patients with GERD were to take either drug on-demand at breakfast or lunchtime, esomeprazole might give faster relief of postprandial symptoms, whereas rabeprazole might be more effective in preventing nocturnal heartburn. Conversely, if the drugs were taken in the evening, esomeprazole's faster onset of action might more effectively relieve nocturnal symptoms. However, clinical trials in patients with GERD would be needed to test those expectations.
We gave both drugs in the morning before breakfast, consistent with how both drugs are often prescribed. A study in GERD patients found that, when rabeprazole 20 mg was given once daily for 7 days, nocturnal intragastric pH did not differ between morning and evening dosing, although nocturnal oesophageal pH was higher after evening dosing.14 Most published studies of on-demand use of PPIs do not specify the time of day that patients take the drug; however, two studies found that 43% and 58% of doses were taken in the morning (between 06:00 and 12:00 hours).12, 13 More data on when patients use PPIs in intermittent and on-demand therapy are needed to assess which drug might be more effective in clinical practice.
Interestingly, our finding that esomeprazole has a faster onset of action does not support the theory that rabeprazole should work faster than other PPIs because of its lower acid stability (higher pKa). The acid stability of a PPI determines both its rate of accumulation in the parietal cell canaliculus, and its rate of conversion to the active sulphenamide form; some authors have argued that it is the higher pKa of rabeprazole (≈5.0, compared with ≈4.0–4.5 for other PPIs) that accounts for its faster onset of action than omeprazole, lansoprazole and pantoprazole, as observed in many studies.2, 15
We found that the effect of esomeprazole on intragastric pH increased more after repeat dosing than did that of rabeprazole. Hence, rabeprazole 10 mg and esomeprazole 20 mg maintained pH >4 for an equivalent duration after a single dose, but, after 5 days’ dosing, esomeprazole 20 mg maintained pH >4 for longer than did rabeprazole 10 mg. Single doses of rabeprazole 20 mg and esomeprazole 40 mg were also equivalent in their effect on 24-h intragastric pH. Although we did not have repeat-dose data for esomeprazole 40 mg, other authors have found that, after 5 days’ dosing, esomeprazole 40 mg maintained pH >4 for longer than did rabeprazole 20 mg.16, 17
Our findings are consistent with those of other studies showing that, whilst the effect of rabeprazole on intragastric pH appears to be close to its maximum after the first dose, the effect of esomeprazole increases over several days of dosing.18, 19 Those differences may reflect differences in the pharmacokinetics of the two PPIs. Rabeprazole exhibits linear kinetics whilst esomeprazole does not; the elimination half-life of esomeprazole, at doses 20–40 mg, increases by about 50% after 5 days’ dosing.3, 20
Combined analyses, or meta-analyses, are often criticized for pooling results from studies done in different populations, or using different methods.21 In addition, meta-analyses are sometimes used to demonstrate an effect that is not present in the individual studies; detractors of meta-analyses argue that, if the effect is of a reasonable size, it should be demonstrable in a single study. We pooled results from three studies performed at the same research unit, by the same investigator and study team, and with nearly identical protocols. There were no significant differences in demographics between the volunteer populations of each study. The outcome variables were the same in each study, and we analysed the original data. Thus, we believe our combined analysis is both justified, and worthwhile. Furthermore, the results of our combined analysis agree with those of the individual studies, giving further support to our conclusions.22, 23
In the pairwise tests between treatments, we did not make any adjustments for multiple comparisons. If such adjustments were made, it is likely that some of our comparisons would not be statistically significant. However, as our studies tested lower doses of rabeprazole than of esomeprazole, we were anxious not to conclude falsely that there was no difference between treatments, as a result of an over-conservative statistical analysis. Indeed, some of the comparisons between rabeprazole 10 mg and esomeprazole 40 mg would not be statistically significant, if an adjustment were made for multiple comparisons. Hence, we feel that our approach was more ‘fair’, because it avoided the risk of failing to identify potential differences between the four treatments.
In conclusion, we have shown that rabeprazole 20 mg increases 24-h intragastric pH more than does esomeprazole 20 mg, after single and repeat doses. Furthermore, single doses of rabeprazole 10 mg and 20 mg are equivalent to esomeprazole 20 mg and 40 mg, respectively, in their effect on pH over 24 h. Thus, over a 24-h period, rabeprazole is more pharmacologically potent than esomeprazole. However, there are differences in the time courses of the effects of the two PPIs: the effect of esomeprazole is faster, whilst that of rabeprazole is more prolonged.
Authors' declaration of personal interests: A. Morocutti is an employee of Eisai Ltd.
Declaration of funding interests: this study was funded in full by Eisai Ltd.