A 3-Part Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DSP-6952 in Healthy Japanese Subjects and Those With ≤3 Spontaneous Bowel Movements per Week.

We hypothesized that DSP-6952, a partial agonist of the 5-hydroxytryptamine type-4 receptor and a gastrointestinal prokinetic agent, can induce natural bowel movements by enhancing gastrointestinal motility and colonic transit in patients with chronic constipation and irritable bowel syndrome with constipation. This 3-part phase 1 study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of DSP-6952. Eighty-eight Japanese subjects (64 healthy volunteers and 24 subjects with spontaneous bowel movements ≤3 times/wk) were randomized to DSP-6952 or placebo. The overall incidence of treatment-emergent adverse events (TEAEs) was similar for DSP-6952 and placebo. The most frequent TEAEs were gastrointestinal disorders; diarrhea was more common with DSP-6952, but only when it was administered to healthy volunteers. Peak plasma concentration (C ) and area under the concentration-time curve (AUC) of DSP-6952 were dose-proportional within a range of 4-120 mg. Under fed conditions, the C and AUC of DSP-6952 were approximately half those of fasting conditions. No abnormal drug accumulation was observed with repeated administration. In subjects with spontaneous bowel movements ≤3 times/wk, the median change in the frequency of bowel movements from baseline increased, although the difference did not reach statistical significance. DSP-6952 was well tolerated at single and multiple doses up to 120 mg/d, with a linear pharmacokinetic profile among all subjects.