A population PK-PD model of YH4808, a novel P-CAB, and intragastric pH that incorporated negative feedback by increased intragastric pH onto the systemic exposure to YH4808

Abstract

YH4808 is a novel potassium-competitive acid blocker that is under clinical development to treat patients with gastroesophageal reflux disease and peptic ulcer diseases. In this study, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of YH4808 were modeled in healthy male volunteers who received a single oral dose of YH4808 at 30, 50, 100, 200, 400, 600, and 800？mg or matching placebo and multiple once-daily oral doses of YH4808 at 100, 200, and 400？mg or matching placebo for 7？days. A population PK？PD model adequately described the time？concentration-effect profiles of YH4808. The maximum increasing effect of YH4808 on intragastric pH was 4.38, which was higher than the observed maximum increase in intragastric pH after omeprazole at 40？mg (2.2 in pH). The maximum inhibitory effect by the increased intragastric pH on the exposure to repeated YH4808 was 58% from baseline. Monte？Carlo simulation experiments based on the final model showed that YH4808 at 200？mg will produce a higher percentage of time at pH >？4 over 24？h on day 1 than observed value of esomeprazole at 40？mg once-daily, an active comparator (84.7% time vs. 58.3% time, respectively). Because YH4808 at ≥200？mg resulted in a higher percentage of time at intragastric pH >？4 than seen after once-daily esomeprazole at 40？mg and YH4808 showed acceptable tolerability at a single-dose of 30？800？mg, we suggest to test the 200？mg once daily dosage regimen in further clinical trials of YH4808.