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Title: Clinical pharmacology of netazepide, a gastrin/CCK-2 receptor antagonist
Author: Boyce, M. J.
ISNI:       0000 0004 6058 9208
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2016
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In non-clinical studies, netazepide (YF476) is a potent, highly-selective and competitive gastrin/CCK2 receptor antagonist (GRA), with good oral bioavailability. In studies involving over 220 healthy subjects, netazepide: • at single doses, caused dose-dependent prolonged increases in gastric pH, but repeated doses led to tolerance; • at single doses, caused dose-dependent inhibition of pentagastrin-induced increases in gastric aspirate volume and acid content, which persisted after repeated doses; • at single doses, was as effective as the PPI rabeprazole at suppressing pentagastrinstimulated gastric acid secretion and increasing serum gastrin; the combination was more effective than either treatment alone in suppressing gastric acid secretion; • reduced plasma CgA – a sign of ECL-cell hypoactivity – whereas rabeprazole increased plasma CgA – a sign of ECL-cell hyperactivity; netazepide also prevented the increase in CgA resulting from rabeprazole-induced hypergastrinaemia; • at low doses, prevented the increase in plasma CgA resulting from esomeprazole-induced hypergastrinaemia; • had dose-proportional and linear pharmacokinetics; • was metabolised mainly to its hydroxy metabolite, TR2, exposure to which was substantial and similar to that of netazepide; and • was safe and well tolerated after single doses up to 400 mg and repeated doses up to 100 mg twice daily for up to 6 weeks. In two studies in a total of 16 patients with autoimmune chronic atrophic gastritis (CAG), achlorhydria, hypergastrinaemia, multiple gastric NETs, and raised circulating CgA, netazepide 50 mg once daily by mouth for 12 weeks: • reduced the number of tumours and size of the largest one; • normalised serum CgA, which returned to pre-treatment levels after stopping netazepide, but did not increase serum gastrin further, confirming that all patients had achlorhydria; • normalised raised mRNA abundancies of gastrin-dependent biomarkers in tumour biopsies, which returned to pre-treatment levels after stopping netazepide; and • suppressed miR-222 overexpression in biopsies of gastric NETs from CAG patients. In an extension of the two studies, after an interval off treatment for a mean 14 (range 8–19) months in which tumours regrew and CgA increased significantly, 13 of the 16 patients took netazepide 25 or 50 mg once daily for another 52 weeks. Netazepide eradicated the tumours of 5 patients. One patient was left with one tumour. Netazepide reduced the number and size of the largest tumour in the other patients. The effect on increased CgA and gastrin was the same as in the 12-week studies. Netazepide was well tolerated. In non-clinical studies, TR2, the main metabolite of netazepide in humans, was not quite as potent as netazepide as a GRA, but was more selective. In healthy subjects, however, TR2 was as potent as netazepide in suppressing pentagastrin-stimulated acid secretion. Furthermore, in healthy subjects, TR2-A, the acetyl derivative of TR2, proved to be a prodrug of TR2 and more bioavailable than either TR2 or netazepide.
Supervisor: Pritchard, D. M. ; Varro, A. Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral