title: Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib.
abstract: Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.
authors: Exelixis, South San Francisco, CA, USA.
authors: Linh
authors: L
authors: Nguyen
authors: Exelixis, South San Francisco, CA, USA.
authors: Jaymes
authors: J
authors: Holland
authors: Exelixis, South San Francisco, CA, USA.
authors: David
authors: D
authors: Ramies
authors: Mamelok Consulting, Palo Alto, CA, USA.
authors: Richard
authors: R
authors: Mamelok
authors: Celerion, Montreal, Quebec, Canada.
authors: Natacha
authors: N
authors: Benrimoh
authors: Celerion, Montreal, Quebec, Canada.
authors: Sabrina
authors: S
authors: Ciric
authors: Orlando Clinical Research Center, Orlando, FL, USA.
authors: Thomas
authors: T
authors: Marbury
authors: Pharmacokinetics & Clinical Research Center, University of Miami, Miami, FL, USA.
authors: Richard A
authors: RA
authors: Preston
authors: Virginia Commonwealth University, Hunter Holmes McGuire VA Medical Center, McGuire Research Institute, Richmond, VA, USA.
authors: Douglas M
authors: DM
authors: Heuman
authors: Virginia Commonwealth University, Hunter Holmes McGuire VA Medical Center, McGuire Research Institute, Richmond, VA, USA.
authors: Edith
authors: E
authors: Gavis
authors: Exelixis, South San Francisco, CA, USA.
authors: Steven
authors: S
authors: Lacy
mesh_terms: D000368:Aged; D000813:Anilides / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D019540:Area Under Curve; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000097:blood* / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051437:Renal Insufficiency / Q000097:blood* / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D020794:Receptor Protein-Tyrosine Kinases
keywords: cabozantinib; hepatic impairment; pharmacokinetics; renal impairment