title: Preclinical pharmacokinetics of the novel PI3K inhibitor GDC-0941 and prediction of its pharmacokinetics and efficacy in human.
abstract: The phosphatidylinositol 3-kinase (PI3K) pathway is a major determinant of cell cycling and proliferation. Its deregulation is associated with the development of many cancers.        GDC-0941, a potent and selective inhibitor of PI3K, was characterised preclinically in in vitro and in vivo studies.        Plasma protein binding was extensive, with free fraction less than 7%, and blood-to-plasma ratio ranged from 0.6 to 1.2 among the species tested. GDC-0941 human hepatic clearance was predicted to be moderate by liver microsomal incubations. GDC-0941 had high permeability in Madin-Darby canine kidney cells.        The clearance of GDC-0941 was high in mouse (63.7 mL/min/kg), rat (49.3 mL/min/kg) and cynomolgus monkey (58.6 mL/min/kg), and moderate in dog (11.9 mL/min/kg). The volume of distribution ranged from 2.52 L/kg in rat to 2.94 L/kg in monkey. Oral bioavailability ranged from 18.6% in monkey to 77.9% in mouse.        Predicted human clearance and volume of distribution using allometry were 6 mL/min/kg and 2.9 L/kg, respectively. The human efficacious doses were predicted based on results from preclinical pharmacokinetic studies and xenograft models.        GDC-0941 preclinical characterisation and predictions of its properties in human supported its progression towards clinical development. GDC-0941 is currently in phase II clinical trials.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Emile G
authors.initials: EG
authors.lastname: Plise
authors.forename: Bilin
authors.initials: B
authors.lastname: Chou
authors.forename: Jason S
authors.initials: JS
authors.lastname: Halladay
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Rudewicz
authors.forename: Qingping
authors.initials: Q
authors.lastname: Tian
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D002250:Carbon Radioisotopes; D002460:Cell Line; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D002250:Carbon Radioisotopes; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D058539:Phosphatidylinositol 3-Kinase