Harvard School of Medicine, Boston, MA, USA.
Takeda Pharmaceuticals International Co., Cambridge, MA, USA.
Aliment Pharmacol Ther. 2021 Aug;54(3):267-280. doi: 10.1111/apt.16451. Epub 2021 Jun 20.
Gastroparesis is a chronic gastric motility disorder. Dopamine D /D receptor antagonists metoclopramide and domperidone are current treatment options but are associated with central nervous system and cardiovascular safety concerns, respectively, precluding chronic use. Trazpiroben (TAK-906), a dopamine D /D receptor antagonist, is under development for chronic treatment of moderate-to-severe gastroparesis. Nonclinical data suggest trazpiroben will have D /D receptor antagonism comparable with metoclopramide or domperidone.
To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics (effect on prolactin and gastric function) of twice-daily trazpiroben (5, 25 and 100 mg) in participants with gastroparesis.
This phase 2a pilot study evaluated gastric emptying using the gastric emptying breath test, with metoclopramide as an internal control. Gastric accommodation and gastroparesis symptoms were assessed using the nutrient drink test and American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, respectively.
Overall, 51 participants were enrolled. Trazpiroben was well tolerated, demonstrating a favourable safety profile without cardiovascular or central nervous system adverse events. All trazpiroben doses were rapidly absorbed and eliminated (t 4-5 hours), and D /D receptor target engagement confirmed by increased serum prolactin (peaking at trazpiroben 25 mg). No effect on gastric emptying was demonstrated with trazpiroben or metoclopramide (P > 0.05), although benefits in volume-to-fullness were seen at trazpiroben 5 mg (P > 0.05) and 25 mg (88.5 vs -26.3 mL; P = 0.019), and nonsignificant numerical aggregate symptom score improvements were observed with trazpiroben 25 mg vs placebo (P = 0.182).
Trazpiroben was well tolerated with a favourable safety profile, supporting its further development for the treatment of gastroparesis. ClinicalTrials.gov identifier: NCT03268941.
胃轻瘫是一种慢性胃动力障碍。多巴胺 D / D 受体拮抗剂甲氧氯普胺和多潘立酮是目前的治疗选择，但分别与中枢神经系统和心血管安全性问题相关，因此不能长期使用。Trazpiroben（TAK-906）是一种多巴胺 D / D 受体拮抗剂，正在开发用于慢性治疗中重度胃轻瘫。非临床数据表明，trazpiroben 将具有与甲氧氯普胺或多潘立酮相当的 D / D 受体拮抗作用。
评估每日两次给予胃轻瘫患者 trazpiroben（5、25 和 100mg）的安全性、耐受性、药代动力学和药效学（对催乳素和胃功能的影响）。
这项 2a 期试点研究使用胃排空呼吸试验评估胃排空，以甲氧氯普胺作为内部对照。使用营养饮料测试评估胃容纳和胃轻瘫症状，以及美国神经胃肠病学和动力学会胃轻瘫 cardinal 症状指数-日常日记分别。
共有 51 名参与者入组。trazpiroben 耐受性良好，具有良好的安全性，无心血管或中枢神经系统不良事件。所有 trazpiroben 剂量均迅速吸收和消除（t 4-5 小时），并通过血清催乳素增加确认 D / D 受体靶标结合（在 trazpiroben 25mg 时达到峰值）。与甲氧氯普胺相比，trazpiroben 对胃排空没有影响（P > 0.05），尽管在 trazpiroben 5mg（P > 0.05）和 25mg（88.5 与 -26.3mL；P = 0.019）时观察到容量到饱的益处，并且与安慰剂相比，trazpiroben 25mg 观察到非显著的综合症状评分改善（P = 0.182）。
trazpiroben 耐受性良好，安全性良好，支持其进一步开发用于治疗胃轻瘫。临床试验.gov 标识符：NCT03268941。
