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- Subjects and methods
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.
- Top of page
- Subjects and methods
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.