title: Population Pharmacokinetic Model of Cabozantinib in Patients with Medullary Thyroid Carcinoma and Its Application to an Exposure-Response Analysis.
abstract: OBJECTIVE
  Cabozantinib is a tyrosine kinase inhibitor approved in the USA and EU for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). The indicated cabozantinib dose is 140 mg/day, with dose modifications allowed for patients who develop adverse events (AEs). The analysis objective was to develop a population pharmacokinetic (PopPK) model in MTC patients and to use the model for exposure-response (ER) analysis of dose modifications.
  
  
  METHODS
  A PopPK model for cabozantinib was developed using data from three clinical trials (2079 evaluations from 289 patients), including a randomized, double-blind, placebo-controlled phase III study of patients with progressive, metastatic MTC. The PopPK model predictions [model-predicted steady-state area under the plasma concentration-time curve (AUCss,pred)] were used for an ER analysis of the time to first dose modification.
  
  
  RESULTS
  The final PopPK model was a one-compartment model with first-order absorption and first-order elimination. Estimated cabozantinib apparent oral clearance (CL/F) and apparent volume of distribution (V c/F) were 106 L/day [±2.98 % relative standard error (RSE)] (males) and 349 L (±2.73 % RSE), respectively. CL/F was reduced by 22 % (to 83 L/day) in females. Sex and body mass index (BMI) were significant covariates that combined contributed 15 % to the variability in cabozantinib CL/F, but did not warrant dose adjustment. Higher cabozantinib AUCss,pred was correlated to an increased risk of early dose modification and a lower average dose through to Day 85. Early cabozantinib dose modification was not associated with a reduction in progression-free survival (PFS).
  
  
  CONCLUSIONS
  A PopPK model was developed for cabozantinib pharmacokinetics in MTC patients. Higher cabozantinib exposure was associated with earlier first dose modification and a lower average administered dose through to Day 85. Early first dose modification did not appear to impact PFS.
authors.affiliation: Genentech (A member of the Roche Group), South San Francisco, CA, USA.|Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA.
authors.forename: Dale
authors.initials: D
authors.lastname: Miles
authors.affiliation: Pharmactuarials LLC, Mountain View, CA, USA.
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Jumbe
authors.affiliation: Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA. slacy@exelixis.com.
authors.forename: Steven
authors.initials: S
authors.lastname: Lacy
authors.affiliation: Exelixis Inc., 210 East Grand Avenue, South San Francisco, CA, 94080-0511, USA.|Medivation Inc., San Francisco, CA, USA.
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000813:Anilides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib