Kitasato University Hospital, Kanagawa, Japan.
Taiho Pharmaceutical Co., Ltd., Tokyo, Japan.
J Clin Pharmacol. 2020 Jun;60(6):702-710. doi: 10.1002/jcph.1583. Epub 2020 Feb 5.
TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibitory potential against cytochrome P450 (CYP) 3A. This open-label, single-group study investigated the effect of TAS-303 on CYP3A activity by evaluating the pharmacokinetics (PK) of single-dose oral simvastatin 5 mg or intravenous midazolam 1 mg after repeated oral administration of TAS-303 3 mg in 12 healthy participants. TAS-303 plus simvastatin resulted in a 1.326-fold and a 1.420-fold increase of simvastatin in peak plasma concentration and area under the plasma concentration-time curve from time zero to time t, where t is the final time of detection (AUC ), respectively. The addition of midazolam resulted in a 1.090-fold increase in the midazolam AUC . TAS-303 had a weak PK interaction with simvastatin but no apparent interaction with midazolam. TAS-303 at 3 mg/day is a weak inhibitor of intestinal but not hepatic CYP3A activity. No clinically important safety concerns related to TAS-303 were raised.
TAS-303（4-哌啶基 2,2-二苯基-2-[丙氧基-1,1,2,2,3,3,3-三]乙酸盐酸盐）是一种新型的选择性去甲肾上腺素再摄取抑制剂，用于治疗压力性尿失禁。一项体外研究和基于生理学的药代动力学模型模拟表明，TAS-303 对细胞色素 P450（CYP）3A 具有抑制潜力。这项开放标签、单组研究通过评估重复口服 TAS-303 3mg 后单次口服辛伐他汀 5mg 或静脉注射咪达唑仑 1mg 的药代动力学（PK），研究了 TAS-303 对 CYP3A 活性的影响，该研究纳入了 12 名健康参与者。TAS-303 加用辛伐他汀使辛伐他汀的峰血浆浓度和从 0 到 t 时间的血浆浓度-时间曲线下面积（AUC）分别增加了 1.326 倍和 1.420 倍，其中 t 是最后检测时间。咪达唑仑的加入使咪达唑仑 AUC 增加了 1.090 倍。TAS-303 与辛伐他汀的 PK 相互作用较弱，但与咪达唑仑无明显相互作用。TAS-303 每天 3mg 是肠道而非肝脏 CYP3A 活性的弱抑制剂。未发现与 TAS-303 相关的临床重要安全性问题。
