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Randomised trial of the effect of a gastrin/CCK2 receptor antagonist on esomeprazole-induced hypergastrinaemia: evidence against rebound hyperacidity

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Abstract

Purpose

Hypergastrinaemia induced by proton pump inhibitor (PPI) therapy may cause ECL-cell and parietal-cell hyperplasia and rebound hyperacidity and dyspepsia after PPI withdrawal. The aim of the study was to assess the effect of different dosage-regimens of netazepide, a gastrin/CCK2 receptor antagonist, on PPI-induced hypergastrinaemia and elevated chromogranin A (CgA).

Methods

Six groups of eight healthy subjects participated in a randomised, double-blind study of esomeprazole 40 mg daily for 28 days, in combination with netazepide 1, 5 or 25 mg or placebo, daily, during the last 14 days of esomeprazole or during 14 days after treatment withdrawal. Fasting serum gastrin and plasma CgA were measured during treatment and after withdrawal, as biomarkers of acid suppression and ECL-cell activity, respectively. Dyspepsia was monitored throughout the study.

Results

Esomeprazole increased gastrin and CgA. Netazepide increased gastrin, but not CgA, and inhibited dose dependently the CgA response to esomeprazole. Gastrin and CgA returned to baseline within 2–3 days of esomeprazole withdrawal; netazepide did not shorten that time. There was no rebound dyspepsia after esomeprazole withdrawal.

Conclusions

Esomeprazole and netazepide each increase gastrin, consistent with a secondary effect of gastric acid suppression, but by different mechanisms. Esomeprazole-induced hypergastrinaemia stimulates ECL cells and thereby increases CgA. Netazepide-induced hypergastrinaemia does not increase CgA, because netazepide blocks gastrin/CCK2 receptors on ECL cells. Co-administration of netazepide 5 mg abolishes the effect of esomeprazole-induced hypergastrinaemia on ECL cells. The quick return to baseline of gastrin and CgA and absence of dyspepsia after esomeprazole withdrawal do not support the concept of rebound hyperacidity.

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Acknowledgements

We thank the volunteers who took part in the study and our many colleagues who helped carry out the study. In particular, we thank Bhavini Ladwa for data management, Torkjel Matzow and Lucy Ball for the study report and Lauren Garden for Figs. 2, 3, 4, 5 and 6.

Authors’ contributions

MB designed and, together with FvdB and SW, carried out the study. TM did the statistical analyses. MB wrote the manuscript. SW and KD contributed to the final version. All authors approved the final version.

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Authors and Affiliations

  1. Hammersmith Medicines Research, Cumberland Avenue, London, NW10 7EW, UK

    Malcolm Boyce, Frans van den Berg, Toni Mitchell, Kate Darwin & Steve Warrington

Authors
  1. Malcolm Boyce
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  2. Frans van den Berg
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  3. Toni Mitchell
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  4. Kate Darwin
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Correspondence to Malcolm Boyce.

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Conflict of interest

MB owns HMR and Trio. SW, FvdB, KD and TM are HMR employees.

Funding

The study was funded by Trio Medicines, London, England (Trio), a subsidiary of Hammersmith Medicines Research (HMR).

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Boyce, M., van den Berg, F., Mitchell, T. et al. Randomised trial of the effect of a gastrin/CCK2 receptor antagonist on esomeprazole-induced hypergastrinaemia: evidence against rebound hyperacidity. Eur J Clin Pharmacol 73, 129–139 (2017). https://doi.org/10.1007/s00228-016-2150-x

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  • DOI: https://doi.org/10.1007/s00228-016-2150-x

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