PI-037

Y. Chen,1 M. Garrett,1 B. I. Rini,2 R. J. Motzer,3 J. P. Dutcher,4 O. Rixe,5 G. Wilding,6 W. Stadler,7 J. Tarazi,1 Y. K. Pithavala1; 1Pfizer, San Diego, CA, 2Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 3Memorial Sloan Kettering Cancer Center, New York, NY, 4Our Lady of Mercy Cancer Center, Bronx, NY, 5University of New Mexico Cancer Center, Albuquerque, NM, 6University of Wisconsin, Madison, WI, 7University of Chicago, Chicago, IL

BACKGROUND: In clinical studies, axitinib, an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, has not been detected in urine. The effect of renal impairment (RI) on axitinib pharmacokinetics (PK) was evaluated in a pooled (n=590 subjects) population PK analysis in patients (pt) with advanced renal cell carcinoma (RCC; n=207) and healthy volunteers (HV; n=383). Axitinib safety categorized by renal function was also assessed in pts (n=350) from a Phase III study in second line RCC.
METHODS: The effect of renal function on axitinib clearance was evaluated in a population PK model. Renal function based on baseline creatinine clearance (CrCL; estimated using the Cockroft & Gault formula) was categorized as: normal renal function (>90 mL/min); mild RI (60-89 mL/min); moderate RI (30-59 mL/min); severe RI (15-29 mL/min); and End-Stage Renal Disease (ESRD; <15 mL/min). The safety of pts (categorized based on baseline CrCL) with severe RI or moderate RI was compared with remaining pts (mild RI & normal renal function).
RESULTS: Renal function (CrCL as continuous variable) was not a significant predictor of axitinib PK, and was not retained in the final population model. The median axitinib CL was 14.0, 10.7, 12.3, 7.81, and 12.6 L/hr in the normal renal function (n=381 including 334 HVs), mild (n=139 including 49 HVs), moderate (n=64), severe (n=5) RI, and ESRD (n=1) groups, respectively. The incidence of ≥ Grade 3 adverse events (AE) in the mild RI plus normal renal function, moderate RI, and severe RI groups was 63%, 77% and 50% respectively. Study discontinuations due to AEs were 10%, 11% and 0% in the three groups.
CONCLUSION: Axitinib PK and safety was similar regardless of renal function. No starting dose adjustment is needed for pts with pre-existing mild to severe RI.