A novel K+ competitive acid blocker, YH4808, sustains inhibition of gastric acid secretion with a faster onset than esomeprazole: randomised clinical study in healthy volunteers

• Published in: Alimentary pharmacology & therapeutics 2017-08, Vol.46 (3), p.337-346
• Main Authors: Yi, S., Lee, H., Jang, S. B., Byun, H. M., Yoon, S. H., Cho, J.‐Y., Jang, I.‐J., Yu, K.‐S.
• Format: Article
• Language: English
• Subjects: Acidity; Acids; Adult; Anti-Ulcer Agents - administration & dosage; Anti-Ulcer Agents - pharmacology; Clinical trials; Cross-Over Studies; Double-Blind Method; Esomeprazole - administration & dosage; Esomeprazole - analogs & derivatives; Esomeprazole - pharmacokinetics; Esomeprazole - pharmacology; Gastric Acid - secretion; Gastroesophageal reflux; Humans; Hydrogen ions; Hydrogen-Ion Concentration; Male; Omeprazole; pH effects; Pharmacodynamics; Pharmacokinetics; Potassium; Randomization; Secretion; Young Adult
• ISSN: 0269-2813; 1365-2036
• DOI: 10.1111/apt.14148

Summary Background YH4808, a K+‐competitive acid blocker, is under clinical development for the treatment of acid‐related disorders, such as gastroesophageal reflux disease. Aims To determine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YH4808, compared to placebo and esomeprazole. Methods This double‐blind, randomised, placebo‐ and active comparator (esomeprazole)‐controlled study was conducted with 123 healthy male volunteers. We evaluated YH4808 (30‐800 mg) properties, administered in single (N=55) and multiple (N=24) oral doses, and recorded the effects on 24‐hour intragastric acidity. Results were compared to placebo (N=20) and esomeprazole 40 mg (N=24). Results Plasma YH4808 exposure increased dose‐proportionally and declined in a multi‐phasic manner. YH4808 ≥200 mg/d maintained intragastric acidity at pH >4 for longer times than esomeprazole during both day and night (%Time at pH >4: >70% vs 58% of a 24‐hour period, respectively; and >50% vs 33% of a 9‐hour night respectively). A twice‐daily regimen of YH4808 more effectively controlled intragastric pH at night than a once‐daily regimen. In evaluating the mean areas under the intragastric pH‐time curves in 15‐minute intervals for 2 hours after dosing, we found that YH4808 had a faster onset than esomeprazole. Moreover, unlike esomeprazole, YH4808 PK and PD were not significantly affected by the CYP2C19 genotype of the subjects. YH4808 was well‐tolerated at all doses administered. Conclusion This study showed that YH4808 produced a rapid, sustained suppression of gastric secretion with good tolerability. The results at YH4808 ≥200 mg/d provide a rationale for further clinical investigations in populations with acid‐related diseases.