A population pharmacokinetic model of cabozantinib in healthy volunteers and patients with various cancer types

Cancer Chemother Pharmacol. 2018 Jun;81(6):1071-1082. doi: 10.1007/s00280-018-3581-0. Epub 2018 Apr 23.


Purpose: An integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in cabozantinib PK across these populations.

Methods: Plasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies.

Results: PK data across studies were adequately characterized by a two-compartment disposition model with dual first- and zero-order absorption processes and first-order elimination. Baseline demographic covariates (age, weight, gender, race, and cancer type) were generally predicted to have a small-to-moderate impact on apparent clearance (CL/F). However, MTC cancer type did show an approximately 93% higher CL/F relative to HVs following chronic dosing, resulting in approximately 40-50% lower predicted steady-state cabozantinib plasma concentrations.

Conclusion: This popPK analysis showed cabozantinib CL/F values to be higher for patients with MTC and may account for the higher dosage required in this patient population (140-mg) to achieve plasma exposures comparable to those in patients with RCC and other tumor types administered a 60-mg cabozantinib tablet dose. Possible factors that may underlie the higher cabozantinib clearance observed in MTC patients are discussed.

Keywords: Cabozantinib; Cancer types; Population pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anilides / administration & dosage*
  • Anilides / pharmacokinetics
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Clinical Trials as Topic
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Male
  • Middle Aged
  • Models, Biological*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Pyridines / administration & dosage*
  • Pyridines / pharmacokinetics
  • Young Adult


  • Anilides
  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • cabozantinib