title: Single oral doses of netazepide (YF476), a gastrin receptor antagonist, cause dose-dependent, sustained increases in gastric pH compared with placebo and ranitidine in healthy subjects.
abstract: BACKGROUND
  Nonclinical studies have shown netazepide (YF476) to be a potent, selective, competitive and orally active gastrin receptor antagonist.
  
  
  OBJECTIVE
  To administer to humans for the first time single oral doses of netazepide, to assess their tolerability, safety, pharmacokinetics and effect on 24-h gastric pH.
  
  
  METHODS
  We did two randomised double-blind single-dose studies in healthy subjects. The first (n = 12) was a six-way incomplete crossover pilot study of rising doses of netazepide (range 0.5-100 mg) and placebo. The second (n = 20) was a five-way complete crossover study of netazepide 5, 25 and 100 mg, ranitidine 150 mg and placebo. In both trials we collected frequent blood samples, measured plasma netazepide and calculated pharmacokinetic parameters. In the comparative trial we measured gastric pH continuously for 24 h and compared treatments by percentage time gastric pH ≥4.
  
  
  RESULTS
  Netazepide was well tolerated. Median t (max) and t (½) for the 100 mg dose were about 1 and 7 h, respectively, and the pharmacokinetics were dose-proportional. Netazepide and ranitidine each increased gastric pH. Onset of activity was similarly rapid for both. All netazepide doses were more effective than placebo (P ≤ 0.023). Compared with ranitidine, netazepide 5 mg was as effective, and netazepide 25 and 100 mg were much more effective (P ≤ 0.010), over the 24 h after dosing. Activity of ranitidine lasted about 12 h, whereas that of netazepide exceeded 24 h.
  
  
  CONCLUSIONS
  In human: netazepide is an orally active gastrin antagonist, and gastrin has a major role in controlling gastric acidity. Repeated-dose studies are justified. NCT01538784 and NCT01538797.
authors.affiliation: Hammersmith Medicines Research, Central Middlesex Hospital, London, UK. mboyce@hmrlondon.com
authors.forename: M
authors.initials: M
authors.lastname: Boyce
authors.forename: O
authors.initials: O
authors.lastname: David
authors.forename: K
authors.initials: K
authors.lastname: Darwin
authors.forename: T
authors.initials: T
authors.lastname: Mitchell
authors.forename: A
authors.initials: A
authors.lastname: Johnston
authors.forename: S
authors.initials: S
authors.lastname: Warrington
mesh_terms: D000328:Adult; D001570:Benzodiazepinones / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005744:Gastric Acid / Q000502:physiology; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011899:Ranitidine / Q000008:administration & dosage; D043887:Receptor, Cholecystokinin B / Q000037:antagonists & inhibitors*
chemical_list: D001570:Benzodiazepinones; D010671:Phenylurea Compounds; D043887:Receptor, Cholecystokinin B; D011899:Ranitidine; C104428:YF 476