title: Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity.
abstract: With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.
authors.affiliation: Oncology Biology, GlaxoSmithKline, 1250 South Collegeville Road, UP1450, Collegeville, PA 19426, USA. rakesh.2.kumar@gsk.com
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Victoria B
authors.initials: VB
authors.lastname: Knick
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Rudolph
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Johnson
authors.forename: Renae M
authors.initials: RM
authors.lastname: Crosby
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Crouthamel
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Hopper
authors.forename: Charles G
authors.initials: CG
authors.lastname: Miller
authors.forename: Laura E
authors.initials: LE
authors.lastname: Harrington
authors.forename: James A
authors.initials: JA
authors.lastname: Onori
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mullin
authors.forename: Tona M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: Anne T
authors.initials: AT
authors.lastname: Truesdale
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Epperly
authors.forename: Amogh
authors.initials: A
authors.lastname: Boloor
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Stafford
authors.forename: Deirdre K
authors.initials: DK
authors.lastname: Luttrell
authors.forename: Mui
authors.initials: M
authors.lastname: Cheung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002474:Cell-Free System; D003315:Cornea / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013450:Sulfones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C580765:GW771806; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013450:Sulfones; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D019000:Phosphotyrosine; C516667:pazopanib; D040262:Receptors, Vascular Endothelial Growth Factor