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A Drug‐Drug Interaction Study to Evaluate the Effect of TAS‐303 on CYP3A Activity in the Small Intestine and Liver
Author(s) -
Kumagai Yuji,
Fujita Tomoe,
Maeda Mika,
Sasaki Yoshinobu,
Nagaoka Makoto,
Huang Jinhong,
Takenaka Toru,
Kawai Masaki
Publication year - 2020
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1583
Subject(s) - cyp3a , midazolam , simvastatin , pharmacokinetics , pharmacology , chemistry , drug interaction , pharmacokinetic interaction , oral administration , cyp3a4 , drug , cytochrome p450 , medicine , metabolism , biochemistry , sedation
TAS‐303 (4‐piperidinyl 2,2‐diphenyl‐2‐[propoxy‐1,1,2,2,3,3,3‐ d 7 ] 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 0‐t ), respectively. The addition of midazolam resulted in a 1.090‐fold increase in the midazolam AUC 0‐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.