Premium
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
Author(s) -
Yumizaki Takuya,
Maeda Mika,
Fujita Tomoe,
Kakuyama Hiroyoshi,
Kumagai Yuji
Publication year - 2020
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.731
Subject(s) - medicine , tolerability , pharmacokinetics , placebo , pharmacodynamics , constipation , adverse effect , defecation , irritable bowel syndrome , area under the curve , gastroenterology , pharmacology , pathology , alternative medicine
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 max ) 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 max 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.