title: Pooled population pharmacokinetic analysis of phase I, II and III studies of linifanib in cancer patients.
abstract: OBJECTIVE
  Linifanib is a multi-targeted receptor tyrosine kinase inhibitor, which can inhibit members of the vascular endothelial growth factor and platelet-derived growth factor receptor families. The objective of this analysis was to characterize the population pharmacokinetics of linifanib in cancer patients.
  
  
  METHODS
  We pooled 7,351 linifanib plasma concentrations from 1,010 cancer patients enrolled in 13 clinical studies. Population pharmacokinetic modelling was performed using NONMEM version 7.2. The covariates that were screened included the cancer type, co-medications, creatinine clearance, formulation, fed status, liver function markers (bilirubin, blood urea nitrogen [BUN], aspartate aminotransferase [AST], alanine aminotransferase [ALT]), albumin, age, sex, race, body weight, surface area and body mass index.
  
  
  RESULTS
  A two-compartment model with first-order absorption and disposition best described linifanib pharmacokinetics. An increase in body weight was associated with less than proportional increases in volumes of distribution. Subjects with hepatocellular carcinoma and renal cell carcinoma were estimated to have 63 and 86% larger volumes of distribution, respectively, than subjects with the other cancer types. Females had 25% slower oral clearance (CL/F) than males, while subjects with colorectal cancer had 41% faster CL/F than other subjects. For linifanib bioavailability, subjects with refractory acute myeloid leukaemia or myelodysplastic syndrome had 43% lower bioavailability, evening doses were associated with 27% lower bioavailability than morning doses, and administration of linifanib under fed conditions decreased the bioavailability by 14%. Finally, the oral solution formulation showed two-fold faster absorption than the tablet formulations.
  
  
  CONCLUSIONS
  The use of mixed-effects modelling allowed robust assessment of the impact of the concomitant effects of body size, different cancer types, formulation, diurnal variation, sex and food on linifanib pharmacokinetics. The developed population pharmacokinetic model describes linifanib concentrations adequately and can be used to conduct simulations or to evaluate the linifanib exposure-response relationship.
authors.affiliation: Clinical Development, AbbVie Inc., 1 North Waukegan Road, AP13A-3, Dept. R4PK, North Chicago, IL, 60064, USA, sale0074@umn.edu.
authors.forename: Ahmed Hamed
authors.initials: AH
authors.lastname: Salem
authors.forename: Denise
authors.initials: D
authors.lastname: Koenig
authors.forename: Dawn
authors.initials: D
authors.lastname: Carlson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D017321:Clinical Trials, Phase I as Topic / Q000706:statistics & numerical data; D017322:Clinical Trials, Phase II as Topic / Q000706:statistics & numerical data; D017326:Clinical Trials, Phase III as Topic / Q000706:statistics & numerical data; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007191:Indazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011153:Population; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012727:Sex Characteristics; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D010671:Phenylurea Compounds; C513486:linifanib; D020794:Receptor Protein-Tyrosine Kinases