title: Single- and multiple-dose disposition kinetics of sunitinib malate, a multitargeted receptor tyrosine kinase inhibitor: comparative plasma kinetics in non-clinical species.
abstract: OBJECTIVE
  The purpose of these extensive non-clinical studies was to assess pharmacokinetics and dispositional properties of sunitinib and its primary active metabolite (SU12662).
  
  
  METHODS
  Sunitinib was administered in single and repeat oral doses in mice, rats, and monkeys. Assessments were made using liquid-chromatography-tandem mass spectrometric methods, radioactive assays, and quantitative whole body autoradiography.
  
  
  RESULTS
  Sunitinib was readily absorbed with good oral bioavailability and linear kinetics at clinically-relevant doses. SU12662 plasma levels were less than those of sunitinib in mice and monkeys, but greater in rats. Sunitinib was extensively distributed with moderate-to-high systemic clearance and eliminated primarily into feces. Single- and repeat-dosing kinetics were similar. A prolonged half-life allowed once-daily dosing, enabling adequate systemic exposure with limited-to-moderate accumulation. In multiple-dose studies with cyclic dosing, drug plasma concentrations cleared from one cycle to the next.
  
  
  CONCLUSIONS
  Sunitinib exhibited advantageous pharmacokinetic and dispositional properties in non-clinical species, translating into favorable properties in humans.
authors.affiliation: Clinical Pharmacology, Roche LLC, Palo Alto, CA 94304, USA.
authors.forename: Joshua O
authors.initials: JO
authors.lastname: Haznedar
authors.forename: Shem
authors.initials: S
authors.lastname: Patyna
authors.forename: Carlo L
authors.initials: CL
authors.lastname: Bello
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Peng
authors.forename: William
authors.initials: W
authors.lastname: Speed
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Yu
authors.forename: Qingling
authors.initials: Q
authors.lastname: Zhang
authors.forename: Juthamas
authors.initials: J
authors.lastname: Sukbuntherng
authors.forename: David J
authors.initials: DJ
authors.lastname: Sweeny
authors.forename: Lida
authors.initials: L
authors.lastname: Antonian
authors.forename: Ellen Y
authors.initials: EY
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000077210:Sunitinib; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib