title: Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors.
abstract: Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non-Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25-72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose-limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100-500 mg dose range, vorinostat area under the concentration-time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached.
authors: Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan.
authors: Yutaka
authors: Y
authors: Fujiwara
authors: Noboru
authors: N
authors: Yamamoto
authors: Yasuhide
authors: Y
authors: Yamada
authors: Kazuhiko
authors: K
authors: Yamada
authors: Tetsuya
authors: T
authors: Otsuki
authors: Shinichi
authors: S
authors: Kanazu
authors: Takashi
authors: T
authors: Iwasa
authors: James S
authors: JS
authors: Hardwick
authors: Tomohide
authors: T
authors: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011379:Prognosis; D015996:Survival Rate; D014018:Tissue Distribution; D000077337:Vorinostat
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat