title: Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics.
abstract: OBJECTIVE
  This study evaluated the preclinical pharmacokinetics (PK) and disposition of fruquintinib (HMPL-013), a small molecule vascular endothelial growth factor receptors inhibitor.
  
  
  METHODS
  In vitro and in vivo PK/ADME assays were conducted. Allometry and PK modeling/simulation were conducted to predict human PK parameters and the time course profiles.
  
  
  RESULTS
  HMPL-013 has high permeability without efflux. It shows moderate oral bioavailability of 42-53 % and Tmax < 4 h in mouse, rat, dog and monkey, with exposure-dose linearity proved in rats and dogs. No significant food effect is on dog PK. HMPL-013 has moderately high tissue distribution. It majorly distributes in gastrointestinal tract, liver, kidney, adrenal and adipose. The plasma protein binding fraction is 88-95 % in mouse, rat, dog and human, invariable up to 10 µM. The in vivo clearance of HMPL-013 is low, consistent with the in vitro scaling. Three major oxidative metabolites were identified in liver microsomes of mouse, rat, dog, monkey and human. Dog is mostly similar to human regarding in vitro metabolism. Demethylation, hydroxylation and sequential glucuronidation are the major in vivo metabolic reactions. Direct urinary and biliary excretion of HMPL-013 is negligible. Metabolizing to M1 (demethylation), sequentially glucuronidating, followed by biliary excretion, and to a less extent, by urinary excretion, are important elimination pathways for HMPL-013 in rats. HMPL-013 has low risk of drug-drug interaction. It is predicted to have favorable human PK properties and low efficacious dose.
  
  
  CONCLUSIONS
  HMPL-013 demonstrates good preclinical PK and enables successful human PK and dose projection. It is valuable for further clinical development.
authors.affiliation: Department of Clinical Pharmacology and DMPK, Hutchison MediPharma Limited, Building 4, 720 Cailun Road, Zhang-Jiang Hi-Tech Park, Shanghai, 201203, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Gu
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Hongcan
authors.initials: H
authors.lastname: Ren
authors.forename: Lixia
authors.initials: L
authors.lastname: Guo
authors.forename: Yang
authors.initials: Y
authors.lastname: Sai
authors.forename: Weihan
authors.initials: W
authors.lastname: Zhang
authors.forename: Weiguo
authors.initials: W
authors.lastname: Su
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001646:Bile / Q000737:chemistry; D001682:Biological Availability; D018938:Caco-2 Cells; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008658:Inactivation, Metabolic; D007408:Intestinal Absorption; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011897:Random Allocation; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D001572:Benzofurans; D065607:Cytochrome P-450 Enzyme Inhibitors; D015507:Drugs, Investigational; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C000591844:HMPL-013; D003577:Cytochrome P-450 Enzyme System; D040262:Receptors, Vascular Endothelial Growth Factor