title: An open-label, single-dose, phase 1 study of the absorption, metabolism and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia.
abstract: 1. Quizartinib absorption, metabolism and excretion were characterized in six healthy men receiving a single oral dose of 60 mg (≈100 μCi) of [14C]-quizartinib. Blood, plasma, urine and faeces were collected ≤336 h postdose. 2. Four hours postdose, maximum mean ± SD blood radioactivity concentrations were 296 ± 67.4 ng equivalents/g. A mean ± SD of 1.64 ± 0.482% and 76.3 ± 6.23% of the dose was recovered in urine and faeces, respectively, within 336 h postdose. 3. Radio-detector high-performance liquid chromatography (radio-HPLC) and liquid chromatography-mass spectrometry (LC-MS) showed two main radioactive peaks in plasma, unchanged quizartinib and mono-oxidative metabolite, AC886. Five additional metabolites in plasma were identified by LC-MS, but low levels prevented radio-HPLC detection. Although unchanged quizartinib was the main radioactive component in faeces (mean, 4.0% of administered dose), 15 metabolites representing a mean of 1.0-3.5% of administered dose were found. Quizartinib was predominantly metabolized by phase I biotransformations (oxidation, reduction, dealkylation, deamination, hydrolysis and combinations thereof). 4. This study indicated that quizartinib was rapidly and orally bioavailable, extensively metabolized, with AC886 as the major circulating metabolite, and predominantly eliminated in faeces. Quizartinib was well tolerated in the subjects.
authors.affiliation: a Covance Laboratories Inc , Madison , WI , USA.
authors.forename: Madhu
authors.initials: M
authors.lastname: Sanga
authors.affiliation: b Lyric Pharmaceuticals, Inc , South San Francisco , CA , USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.affiliation: a Covance Laboratories Inc , Madison , WI , USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Marini
authors.affiliation: c Daiichi Sankyo, Inc , San Diego , CA , USA , and.
authors.forename: Guy
authors.initials: G
authors.lastname: Gammon
authors.affiliation: d Covance Clinical Research Unit , Madison , WI , USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Hale
authors.affiliation: c Daiichi Sankyo, Inc , San Diego , CA , USA , and.
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
mesh_terms: D052160:Benzothiazoles / Q000378:metabolism* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D010671:Phenylurea Compounds / Q000378:metabolism* / Q000627:therapeutic use
chemical_list: D052160:Benzothiazoles; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; C544967:quizartinib
keywords: Absorption; FLT3 tyrosine kinase inhibitor; acute myeloid leukemia; excretion; metabolism; quizartinib