title: Disposition and metabolism of 14C-dovitinib (TKI258), an inhibitor of FGFR and VEGFR, after oral administration in patients with advanced solid tumors.
abstract: OBJECTIVE
  This study investigated the metabolism and excretion of dovitinib (TKI258), a tyrosine kinase inhibitor that inhibits fibroblast, vascular endothelial, and platelet-derived growth factor receptors, in patients with advanced solid tumors.
  
  
  METHODS
  Four patients (cohort 1) received a single 500 mg oral dose of (14)C-dovitinib, followed by the collection of blood, urine, and feces for ≤10 days. Radioactivity concentrations were measured by liquid scintillation counting and plasma concentrations of dovitinib by liquid chromatography-tandem mass spectrometry. Both techniques were applied for metabolite profiling and identification. A continuous-dosing extension phase (nonlabeled dovitinib 400 mg daily) was conducted with the 3 patients from cohort 1 and 9 additional patients from cohort 2.
  
  
  RESULTS
  The majority of radioactivity was recovered in feces (mean 61 %; range 52-69 %), as compared with urine (mean 16 %; range 13-21 %). Only 6-19 % of the radioactivity was recovered in feces as unchanged dovitinib, suggesting high oral absorption. (14)C-dovitinib was eliminated predominantly via oxidative metabolism, with prominent primary biotransformations including hydroxylation on the fluorobenzyl ring and N-oxidation and carbon oxidation on the methylpiperazine moiety. Dovitinib was the most prominent radioactive component in plasma. The high apparent volume of distribution (2,160 L) may indicate that dovitinib distributes extensively to tissues. Adverse events were predominantly mild to moderate, and most common events included nausea, vomiting, constipation, diarrhea, and fatigue.
  
  
  CONCLUSIONS
  Dovitinib was well absorbed, extensively distributed, and eliminated mainly by oxidative metabolism, followed by excretion, predominantly in feces. The adverse events were as expected for this class of drug.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Louwesweg 6, Amsterdam, The Netherlands. a.c.dubbelman@gmail.com
authors.forename: Anne-Charlotte
authors.initials: AC
authors.lastname: Dubbelman
authors.forename: Alana
authors.initials: A
authors.lastname: Upthagrove
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Serena
authors.initials: S
authors.lastname: Marchetti
authors.forename: Eugene
authors.initials: E
authors.lastname: Tan
authors.forename: Kimberly
authors.initials: K
authors.lastname: Krone
authors.forename: Suraj
authors.initials: S
authors.lastname: Anand
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D015363:Quinolones / Q000009:adverse effects / Q000493:pharmacokinetics*; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D017468:Receptors, Fibroblast Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor