PII-088

S. Ciric,1 R. Preston,2 D. M. Heuman,3 T. C. Marbury,4 J. Holland,5 R. D. Mamelok,6 N. Benrimoh,1 D. A. Ramies,5 E. Gavis,7 S. Lacy,5 L. T. Nguyen5; 1Celerion, Saint-Laurent (Montreal), QC, Canada, 2University of Miami, Miami, FL, 3Virginia Commonwealth University, Richmond, VA, 4Orlando Clinical Research Center, Orlando, FL, 5Exelixis, Inc., South San Francisco, CA, 6Mamelok Consulting, Palo Alto, CA, 7McGuire VAMC, Richmond, VA

BACKGROUND: Cabozantinib (Cabo) is approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. [14C]-Cabo radioactivity is eliminated in feces (~54%) and urine (~27%) over 48 days postdose. Two studies were conducted to assess pharmacokinetics (PK) of Cabo in renal- or hepatic-impaired subjects.
METHODS: Study 1 enrolled 10 subjects with mild or moderate impairment of renal function and 12 healthy controls matched for age, gender, and body mass index (BMI) to the moderate group. Study 2 enrolled 8 males with mild or moderate hepatic impairment and 10 healthy males matched for age, BMI, and ethnicity. Based on safety and PK data, severely hepatic-impaired subjects were not enrolled. All subjects received one 60 mg (free base) dose followed by PK sampling over 21 days. Plasma concentration and protein binding of Cabo were determined by LC/MS-MS and equilibrium dialysis, respectively. PK parameters were computed using non-compartmental methods.
RESULTS:
StudyComparisonParameterGeometric Mean
Ratios (%) (test/reference)
90% Confidence Intervals (CI)Effect of Renal or Hepatic Impairment
Study 1 Renal ImpairmentMild vs ControlCmax (ng/mL)119.3591.60, 155.51No clinically significant effect: 90% CI within [50-200%] boundaries
AUC0-inf (ng*hr/mL)130.0798.79, 171.26
Moderate vs ControlCmax (ng/mL)102.4778.64, 133.52
AUC0-inf (ng*hr/mL)105.6179.61, 140.11
Study 2 Hepatic ImpairmentMild vs ControlCmax (ng/mL)110.4082.37-147.97AUC 81% higher
AUC0-inf (ng*hr/mL)181.19121.44-270.34
Moderate vs ControlCmax (ng/mL)70.9170.91-95.38AUC 63% higher
AUC0-inf (ng*hr/mL)162.74107.37-246.67

In each study, % unbound drug was slightly higher in the moderately impaired cohort.
CONCLUSION: Cabo can be administered without dose adjustment in patients with mild/moderate renal impairment but requires monitoring for toxicity and potential dose adjustment in hepatic-impaired patients.