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- Title
A Drug‐Drug Interaction Study to Evaluate the Effect of TAS‐303 on CYP3A Activity in the Small Intestine and Liver.
- Authors
Kumagai, Yuji; Fujita, Tomoe; Maeda, Mika; Sasaki, Yoshinobu; Nagaoka, Makoto; Huang, Jinhong; Takenaka, Toru; Kawai, Masaki
- Abstract
TAS‐303 (4‐piperidinyl 2,2‐diphenyl‐2‐[propoxy‐1,1,2,2,3,3,3‐d7] 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 (AUC0‐t), respectively. The addition of midazolam resulted in a 1.090‐fold increase in the midazolam AUC0‐t. 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.
- Subjects
DRUG interactions; SMALL intestine; LIVER; MIDAZOLAM; NORADRENALINE; SIMVASTATIN; CYTOCHROME P-450
- Publication
Journal of Clinical Pharmacology, 2020, Vol 60, Issue 6, p702
- ISSN
0091-2700
- Publication type
Article
- DOI
10.1002/jcph.1583