Effect of Renal and Hepatic Impairment on the Pharmacokinetics of Cabozantinib

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 renal- or hepatic-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 (GLS) mean ratios for plasma cabozantinib AUC0-inf 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 % 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. This article is protected by copyright. All rights reserved.

Journal of clinical pharmacology. 2016 Feb 11 [Epub ahead of print]

Linh Nguyen, Jaymes Holland, David Ramies, Richard Mamelok, Natacha Benrimoh, Sabrina Ciric, Thomas Marbury, Richard A Preston, Douglas M Heuman, Edith Gavis, Steven Lacy

Exelixis, Inc. , 210 East Grand Avenue, So, San Francisco, CA, USA, 94083. , Exelixis, Inc. , 210 East Grand Avenue, So, San Francisco, CA, USA, 94083. , Exelixis, Inc. , 210 East Grand Avenue, So, San Francisco, CA, USA, 94083. , Mamelok Consulting, 364 Churchill Avenue, Palo Alto, CA, USA, 94301-3601. , Celerion, 100 Alexis-Nihon, Room 360, Montreal, QC, Canada, H4M 2N8. , Celerion, 100 Alexis-Nihon, Room 360, Montreal, QC, Canada, H4M 2N8. , Orlando Clinical Research Center, 5055 South Orange Ave, Orlando, Florida, USA, 32809. , Pharmacokinetics & Clinical Research Center, University of Miami, 1500 N. W. 12th Ave, 15th floor, Miami, Florida, USA, 33136. , Virginia Commonwealth University, Hunter Holmes McGuire DVA Medical Center, McGuire Research Institute. , Virginia Commonwealth University, Hunter Holmes McGuire DVA Medical Center, McGuire Research Institute. , Exelixis, Inc. , 210 East Grand Avenue, So, San Francisco, CA, USA, 94083.

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