title: Population pharmacokinetics modeling and analysis of foretinib in adult patients with advanced solid tumors.
abstract: Foretinib is a multikinase inhibitor that inhibits multiple receptor tyrosine kinases, including MET and VEGFR, with the potential for treatment of solid tumors. Hepatocellular carcinoma (HCC) pathogenesis is associated with overexpression of MET, and physiologic changes in the livers of HCC patients may decrease CYP3A isozyme-mediated metabolism of foretinib. A population pharmacokinetic model of foretinib was developed to explore the effect of tumor type, formulation, and other covariates. Data from 1 HCC study in Asia and 3 non-HCC studies in the United States with varying foretinib regimens and formulations were used for analysis. A 2-compartment model with a linear first-order absorption and elimination and lag time in absorption adequately described foretinib pharmacokinetics in 132 advanced non-HCC and HCC patients and identified an effect of formulations on bioavailability. The bisphosphate salt capsules and freebase tablets had a relative bioavailability 37% and 20% higher, respectively, than the solution formulation. HCC patients had ≈19.6% lower mean clearance (70.14 L/h), ≈16% lower mean volume of distribution (1725.6 L), and higher dose-normalized exposure compared with non-HCC patients. This could be a result of differences in metabolism in HCC patients, body weight, or activity of CYP3A isozymes between Asian and Western cancer patients.
authors.affiliation: Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Rajendra P
authors.initials: RP
authors.lastname: Singh
authors.affiliation: Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Bela
authors.initials: B
authors.lastname: Patel
authors.affiliation: Oncology Clinical Development, GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Kallender
authors.affiliation: Eisai Limited, Hertfordshire, UK; formerly of Oncology Clinical Development, GlaxoSmithKline, Stockley Park, UK.
authors.forename: Lone H
authors.initials: LH
authors.lastname: Ottesen
authors.affiliation: Oncology Clinical Development, GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Laurel M
authors.initials: LM
authors.lastname: Adams
authors.affiliation: Clinical Pharmacology Modeling & Simulation, GlaxoSmithKline, King of Prussia, PA, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Cox
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000097:blood / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D011804:Quinolines / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; C544831:GSK 1363089; D047428:Protein Kinase Inhibitors; D011804:Quinolines
keywords: foretinib; hepatocellular carcinoma; population pharmacokinetics; solid tumors