Effect of Renal Impairment on the Pharmacokinetics and Safety of Axitinib.

Abstract

Axitinib, an inhibitor of vascular endothelial growth factor (VEGF) receptors, is approved as second-line treatment for advanced renal cell carcinoma (RCC). Agents targeting the VEGF pathway may induce renal toxicities, which may be influenced by pre-existing renal dysfunction. The objective was to characterize axitinib pharmacokinetics and safety in patients with renal impairment. Effect of renal function (baseline creatinine clearance [CrCL]) on axitinib clearance was evaluated in a population pharmacokinetic model in 207 patients with advanced solid tumors who received a standard axitinib starting dose, and in 383 healthy volunteers. Axitinib safety according to baseline CrCL was assessed in previously treated patients with RCC (n = 350) who received axitinib in the phase 3 AXIS study. Median axitinib clearance was 14.0, 10.7, 12.3, 7.81, and 12.6L/h, respectively, in individuals with normal renal function (≥90ml/min; n = 381), mild renal impairment (60-89ml/min; n = 139), moderate renal impairment (30-59ml/min; n = 64), severe renal impairment (15-29ml/min; n = 5), and end-stage renal disease (<15ml/min; n = 1). The population pharmacokinetic model adequately predicted axitinib clearance in individuals with severe renal impairment or end-stage renal disease. Grade ≥3 adverse events (AEs) were reported in 63% of patients with normal renal function or mild impairment, 77% with moderate impairment, and 50% with severe impairment; study discontinuations due to AEs were 10%, 11%, and 0%, respectively. Axitinib pharmacokinetics and safety were similar regardless of baseline renal function; no starting-dose adjustment is needed for patients with pre-existing mild to severe renal impairment.