Background Nonclinical studies have shown netazepide (YF476) to be a potent, selective, competitive and orally active gastrin receptor antagonist. Aim 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 similar to=similar to 12) was a six-way incomplete crossover pilot study of rising doses of netazepide (range 0.5100 similar to mg) and placebo. The second (n similar to=similar to 20) was a five-way complete crossover study of netazepide 5, 25 and 100 similar to mg, ranitidine 150 similar to 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 similar to h and compared treatments by percentage time gastric pH =4. Results Netazepide was well tolerated. Median t max and t 1/2 for the 100 similar to mg dose were about 1 and 7 similar to 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 similar to=similar to 0.023). Compared with ranitidine, netazepide 5 similar to mg was as effective, and netazepide 25 and 100 similar to mg were much more effective (P similar to=similar to 0.010), over the 24 similar to h after dosing. Activity of ranitidine lasted about 12 similar to h, whereas that of netazepide exceeded 24 similar to 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.
