A Phase 1 Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of DS‐3801b, a Motilin Receptor Agonist, in Healthy Subjects

DS‐3801b is an orally active, nonmacrolide, selective motilin receptor agonist. The aim of this 2‐part first‐in‐human study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects on proximal and distal gastrointestinal (GI) motility of single oral doses of DS‐3801b in healthy subjects. The 13C‐octanoate breath test was used to assess gastric emptying (GE), a measure of proximal GI motility. The time to first bowel movement (TTFBM) and the consistency of the first bowel movement according to the Bristol Stool Scale (BSS) were recorded to assess distal GI motility. In part A, 48 subjects received single oral doses of DS‐3801b from 1 to 100 mg or placebo (6 DS‐3801b, 2 placebo per cohort). In part B, 12 subjects received 50 mg of DS‐3801b or placebo to assess GE. DS‐3801b is safe and generally well tolerated after doses up to 50 mg, resulting in mild, predominantly GI adverse events. DS‐3801a plasma concentrations increase with increasing doses; however, Cmax increases greater than dose‐proportionally, whereas AUC increases less than dose‐proportionally. The double peaks observed are consistent with multiple absorption sites. Results of the 13C‐octanoate breath test indicate that DS‐3801b accelerates GE. Fifty milligrams of DS‐3801b resulted in a 20.8% median reduction in GE T1/2 and a 20.6% median reduction in GE Tlag compared with placebo. However, this increase in proximal GI motility was not accompanied by an effect on distal GI motility, as indicated by no significant differences in TTFBM and BSS values across DS‐3801b dose levels or compared with placebo.