title: Mass balance, pharmacokinetics, and metabolism of linsitinib in cancer patients.
abstract: OBJECTIVE
  This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in those patients who wished to continue treatment beyond the single (14)C-linsitinib dose.
  
  
  METHODS
  Five patients received a single oral dose of 150 mg (14)C-linsitinib, followed by collection of blood, plasma, urine, and feces for 10 days. The collected material was analyzed for total radioactivity, linsitinib, and metabolites. The safety of 150 mg of unlabeled linsitinib administered twice daily until disease progression was also assessed.
  
  
  RESULTS
  The median time to reach the maximum plasma concentration of linsitinib was 3.0 h, median maximum plasma concentration was 1789 ng/mL, median terminal half-life was 2.4 h, and median apparent oral clearance was 12.45 L/h. After a single dose of (14)C-linsitinib, 5.44 and 76.4 % of mean total radioactivity administered were recovered in urine and feces, respectively. Eighteen linsitinib metabolites (M1-M18) were detected in plasma, urine, and feces samples, and their structures were elucidated. The main metabolic reactions of linsitinib in humans were oxidation and sulfate conjugation. Linsitinib was well tolerated after a single dose of (14)C-linsitinib, and fatigue was the most frequent adverse event following multiple doses of unlabeled linsitinib.
  
  
  CONCLUSIONS
  (14)C-linsitinib is rapidly absorbed and extensively metabolized. Linsitinib excretion via bile into feces is the predominant elimination route from plasma with minor renal elimination.
authors.affiliation: Astellas Pharma US Inc, 1 Astellas Way, Northbrook, IL, 60062, USA. Srinivasu.poondru@astellas.com.
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Poondru
authors.affiliation: Northwest Medical Specialties, Tacoma, WA, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Chaves
authors.affiliation: Astellas Pharma US Inc, 1 Astellas Way, Northbrook, IL, 60062, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Yuen
authors.affiliation: Planet Pharma, Northbrook, IL, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Parker
authors.affiliation: Astellas Research Institute of America, Skokie, IL, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Conklin
authors.affiliation: Astellas Pharma US Inc, 1 Astellas Way, Northbrook, IL, 60062, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Singh
authors.affiliation: Astellas Research Institute of America, Skokie, IL, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Nagata
authors.affiliation: Astellas Pharma US Inc, 1 Astellas Way, Northbrook, IL, 60062, USA.
authors.forename: Stanley
authors.initials: S
authors.lastname: Gill
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D011719:Pyrazines / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines
keywords: IGF-1R/IR inhibitor; Linsitinib; Mass balance of linsitinib; Pharmacokinetics of linsitinib