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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.

Abstract YH12852, a novel, highly selective 5‐hydroxytryptamine 4 (5‐HT4) receptor agonist, is currently under development to treat patients with functional constipation. In this study, we aimed to develop a pharmacokinetic (PK)–pharmacodynamic (PD) model that adequately described the time courses of the plasma concentrations of YH12852 and its prokinetic effect as assessed by the Gastric Emptying Breath Test (GEBT) and to predict the prokinetic effect of YH12852 at higher doses through PD simulation. We used the plasma concentrations of YH12852 from patients with functional constipation and healthy subjects and the GEBT results from healthy subjects obtained from a phase I/IIa trial. The PK‐PD modeling and covariate analysis were performed using NONMEM software. The prokinetic effect of YH12852 was described using a semimechanistic multicompartment PD model and an empirical model by Ghoos et al. A two‐compartment model with first‐order absorption adequately described the observed concentration‐time profiles of YH12852. The semimechanistic multicompartment PD model and the revised Ghoos model with two slope parameters adequately described the observed kPCDt (the percent dose of 13C excreted in the exhaled air at minute t after completing the test meal, multiplied by 1000) values. YH12852 accelerated gastric emptying even at low doses of 0.05–0.1 mg, and its prokinetic effect was greater in subjects suffering from more severe functional constipation. The PD simulation experiments revealed that the change from baseline in the half time for gastric emptying induced by YH12852 increased in a dose‐dependent manner at 0.05–5 mg although the results at doses >0.1 mg were extrapolated. We also showed that the empirical Ghoos model is a special case of the general semimechanistic multicompartment PD model for gastric emptying.

Gastrointestinal (GI) motility disorders are common, decreases quality of life, and imposes a substantial economic burden. YH12852 is a novel agonist of 5‐hydroxytryptamine for the treatment of GI motility disorders. This phase I/IIa study assessed the tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) profiles of YH12852. In the multiple dose (MD) cohort, healthy subjects and patients with functional constipation were randomized and received orally YH12852 at 0.3, 0.5, 1, 2, or 3 mg or prucalopride 2 mg or their matching placebo, once daily for 14 days after breakfast. In the multiple low‐dose cohort (MLD), healthy subjects randomly received once‐daily oral doses of YH12852 at 0.05 or 0.1 mg for 14 days after breakfast. Questionnaires, gastric emptying breath test for PDs, and plasma samples for PKs were collected. In the MD cohort, a total of 56 subjects (29 healthy volunteers and 27 patients with functional constipation) were randomized, of whom 48 completed the study. In the MLD cohort, a total of 16 healthy subjects were randomized, and 15 subjects completed the study. YH12852 increased the average weekly frequency of spontaneous bowel movements and loosened the stool. In addition, YH12852 increased quality of life satisfaction, and decreased severity of constipation symptom and GI symptoms. YH12852 was safe and well‐tolerated up to 3 mg and showed nearly dose proportional PKs. In conclusion, YH12852 was safe and enhanced GI motility. YH12852 can be developed as an effective treatment option for GI motility disorders, including functional constipation. Further studies are warranted to confirm this possibility.