Immediate‐release oral proton pump inhibitors: Panacea or a flash in the pan?

Abstract

Use of proton pump inhibitors (PPI) after endoscopic hemostatic treatment of bleeding peptic ulcers is a standard therapy for preventing early re-bleeding.1 However, controversy continues regarding the optimal dose and route of administration of PPI.2 While both i.v. and oral PPI are effective in preventing early re-bleeding, meta-analysis of randomized trials found that i.v. infusion of high-dose PPI is superior to low-dose (i.e. oral or repeated i.v. injections) PPI in terms of the need for surgery.1 Oral PPI have two major limitations: a slow onset of action and failure to maintain a stably high intragastric pH. One attempt to overcome the limitations of conventional oral PPI is the development of immediate-release (IR) formulations. In this issue, Banerjee et al.3 shows that healthy volunteers who received buffered IR esomeprazole 40 mg p.o. had superior intragastric pH profile compared to those who received i.v. pantoprazole 40 mg every 12 h for 24 h. After the first dose of buffered IR esomeprazole, the intragastric pH was rapidly raised to 6 in a median time of 2 min whereas it took 80 min for i.v. pantoprazole to achieve this level of intragastric pH. Furthermore, the mean percentage time to an intragastric pH of more than 6.0 was 91% in the buffered IR esomeprazole group compared to 20% in the i.v. pantoprazole group in a 24-h period. While many readers would agree that the intragastric pH profile achieved by buffered IR esomeprazole was close to perfection, was the result too good to be true? The rapid rise in intragastric pH with buffered IR esomeprazole was not unexpected because the bicarbonate content of the formulation would neutralize gastric acid. Similar findings were also reported in an earlier study with buffered IR omeprazole.4 In the previous study, however, IR omeprazole rarely raised the intragastric pH above 6 (reported median 24-h intragastric pH was 3.7 only).4 By contrast, the reported median 24-h intragastric pH was 6.18 with IR esomeprazole in the current study.3 In fact, the pH profile achieved by IR esomeprazole was comparable to that with continuous infusion of high-dose PPI.5 What factors could possibly account for such impressive results with just two p.o. doses of IR esomeprazole in 24 h? One could argue that esomeprazole is superior to omeprazole because the former has a better pharmacodynamic profile. The modest advantage of esomeprazole over omeprazole, however, is unlikely to explain the striking difference between the current and earlier studies.3,4 When interpreting the effects of PPI on intragastric pH, one needs to be aware of factors that may influence the outcome. Helicobacter pylori infection is well known to enhance the acid-suppressing effect of PPI.6 Investigators often recognize the importance of excluding H. pylori infection in pH studies. However, a negative rapid urease test does not exclude hypochlorhydria in patients with past H. pylori infection. In Asian countries where the prevalence of H. pylori infection is high, a considerable proportion of the population with hypochlorhydria associated with past H. pylori infection is not unexpected. It would be useful to know the proportion of subjects with hypochlorhydria or histological evidence of gastric atrophy when interpreting pH studies. Another factor is gastric parietal cell mass. PPI are thought to be more effective in Asians because of the smaller parietal cell mass. Small parietal cell mass may partly explain the observation that PPI reduce mortality associated with peptic ulcer bleeding in Asian studies but not in Western studies.1 Presumably, the study by Banerjee et al.3 was conducted in Indian subjects whereas the IR omeprazole study was done on white subjects.4 The efficacy of PPI is also influenced by genetic polymorphism of certain human drug-metabolizing cytochrome P450 (CYP) enzymes. In particular, polymorphism of CYP2C19 has been reported to affect the efficacy of some PPI,7 and substantial racial difference exists in terms of the relative proportions of extensive and poor metabolizers.8 Unlike other PPI such as omeprazole, the CYP2C19 genetic polymorphism is thought to have little influence on the disposition of esomeprazole.9 Surprisingly, a recent study found that the intragastric pH and plasma level of esomeprazole was affected by the CYP2C19 genotype status, and that a multiple dosing regimen of oral esomeprazole improved acid control compared to a single daily regimen.10 In summary, there is little doubt that buffered IR PPI have certain advantages. Whether they are an alternative to i.v. infusion of high-dose PPI in patients with bleeding peptic ulcers can only be addressed by large-scale, head-to-head trials using predefined clinical outcomes. Until further data are available, i.v. infusion of high-dose PPI after endoscopic treatment of bleeding peptic ulcers remains the most studied and best proven strategy.