title: Safety, tolerability and pharmacokinetics of TAS-108, a novel anti-oestrogen, in healthy post-menopausal Japanese women: a phase I single oral dose study.
abstract: TAS-108 is a novel steroidal anti-oestrogen, expected to be useful for the treatment of breast cancer. The present study was conducted to investigate the safety, tolerability and pharmacokinetics of TAS-108 following the administration at a single oral dose of 40 mg to up to 120 mg in 12 post-menopausal women and the effect of food on the pharmacokinetics of the drug. All adverse events were mild and involved transient symptoms that resolved without therapeutic intervention. TAS-108 was readily absorbed and plasma levels of TAS-108 steadily declined, apparently in a multi-exponential manner. C(max) and AUC(0-12) were proportionally increased with increasing dose of TAS-108. The C(max) and AUC(0-t) of TAS-108 and its metabolite, deEt-TAS-108, were significantly increased to approximately 150% when TAS-108 was administered after a meal. Food did not affect the elimination half-life of TAS-108 or its metabolites. In this escalating dose-study of TAS-108, the drug was well tolerated by healthy post-menopausal Japanese women. The pharmacokinetics of TAS-108 indicated dose proportionality, and its bioavailability was significantly increased by food intake.
authors.affiliation: Clinical Investigation Center, Kitasato University East Hospital, 2-1-1, Asamizodai, Sagamihara, Kanagawa 228-8520, Japan. kuma-guy@za2.so-net.ne.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Tomoe
authors.initials: T
authors.lastname: Fujita
authors.forename: Machiko
authors.initials: M
authors.lastname: Ozaki
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Yokota
authors.forename: Mika
authors.initials: M
authors.lastname: Maeda
authors.forename: Mizue
authors.initials: M
authors.lastname: Shida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Otani
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Yamaya
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsuruta
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D001943:Breast Neoplasms / Q000378:metabolism / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D006801:Humans; D007564:Japan; D008875:Middle Aged; D017698:Postmenopause / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D004967:Estrogens; C482068:TS 108; D004958:Estradiol