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Abstract：
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 (Cmax ) 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 Cmax 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.
摘要：
我们假设DSP-6952，5-羟色胺4型受体的部分激动剂和胃肠促动力剂，可以通过增强慢性便秘和便秘型肠易激综合征患者的胃肠动力和结肠运输来诱导自然排便。这项由3部分组成的第一阶段研究评估了安全性，耐受性,以及DSP-6952的药代动力学和药效学特征。88名日本受试者（64名健康志愿者和24名自发排便≤3次/周的受试者）被随机分配到DSP-6952或安慰剂。DSP-6952和安慰剂的治疗引起的不良事件（TEAE）的总发生率相似。最常见的TEAE是胃肠道疾病；腹泻在DSP-6952中更为常见，但仅限于对健康志愿者施用。DSP-6952的峰值血浆浓度（Cmax）和浓度-时间曲线下面积（AUC）在4-120mg范围内与剂量成正比。在美联储的条件下，DSP-6952的Cmax和AUC约为空腹时的一半.重复给药没有观察到异常的药物积累。在自发排便≤3次/周的受试者中，与基线相比，排便频率的中位数变化增加，尽管差异没有达到统计学意义。DSP-6952在单次和多次剂量高达120mg/d时耐受性良好，在所有受试者中具有线性药代动力学特征。
