title: Bioavailability, metabolism and disposition of oral pazopanib in patients with advanced cancer.
abstract: 1. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor that was recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. 2. In this two-part study, we investigated the metabolism, disposition of [(14)C]pazopanib, and the oral bioavailability of pazopanib tablets in patients with advanced cancer. 3. In part A, three men each received a single oral dose of [(14)C]pazopanib in suspension (400 mg, 70 µCi). Pazopanib was the predominant drug-related component in circulation. Two metabolites derived from hydroxylation and one from N-demethylation were also circulating, but were minor, each accounting for <5% of plasma radioactivity. Faecal elimination predominated, accounting for 82.2% of the administered radio-dose, with negligible renal elimination (2.6% of dose). Pazopanib was primarily excreted as the unchanged drug in faeces (67% of dose). 4. In part B, seven additional patients received a single intravenous administration of 5 mg pazopanib (day 1) followed by oral administration of 800 mg pazopanib tablet once daily for 26 days (days 3 or 5-28). In the three evaluable patients from part B, pazopanib had a slow plasma clearance and a small volume of distribution. The absolute oral bioavailability of the 800 mg pazopanib tablet ranged from 14% to 39%.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA. yanli.2.deng@gsk.com
authors.forename: Yanli
authors.initials: Y
authors.lastname: Deng
authors.forename: Caroline
authors.initials: C
authors.lastname: Sychterz
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Dar
authors.forename: David
authors.initials: D
authors.lastname: Bershas
authors.forename: Kitaw
authors.initials: K
authors.lastname: Negash
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Qian
authors.forename: Emile P
authors.initials: EP
authors.lastname: Chen
authors.forename: Peter D
authors.initials: PD
authors.lastname: Gorycki
authors.forename: May Y K
authors.initials: MY
authors.lastname: Ho
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002250:Carbon Radioisotopes; D006801:Humans; D007191:Indazoles; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D020533:Angiogenesis Inhibitors; D002250:Carbon Radioisotopes; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib