Ying Chen1, Brian I Rini2, Robert J Motzer3, Janice P Dutcher4, Olivier Rixe5, George Wilding6, Walter M Stadler7, Jamal Tarazi1, May Garrett1, Yazdi K Pithavala8,9. 1. Pfizer Oncology, San Diego, CA, USA. 2. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA. 3. Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. New York Medical College, Valhalla, NY, USA. 5. University of New Mexico Cancer Center, Albuquerque, NM, USA. 6. University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI, USA. 7. Department of Medicine, University of Chicago, Chicago, IL, USA. 8. Pfizer Oncology, San Diego, CA, USA. yazdi.pithavala@pfizer.com. 9. Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA. yazdi.pithavala@pfizer.com.
Abstract
BACKGROUND: 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. OBJECTIVE: The objective was to characterize axitinib pharmacokinetics and safety in patients with renal impairment. PATIENTS AND METHODS: 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. RESULTS: Median axitinib clearance was 14.0, 10.7, 12.3, 7.81, and 12.6 L/h, respectively, in individuals with normal renal function (≥90 ml/min; n = 381), mild renal impairment (60-89 ml/min; n = 139), moderate renal impairment (30-59 ml/min; n = 64), severe renal impairment (15-29 ml/min; n = 5), and end-stage renal disease (<15 ml/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. CONCLUSIONS: 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.
BACKGROUND: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. OBJECTIVE: The objective was to characterize axitinib pharmacokinetics and safety in patients with renal impairment. PATIENTS AND METHODS: 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. RESULTS: Median axitinib clearance was 14.0, 10.7, 12.3, 7.81, and 12.6 L/h, respectively, in individuals with normal renal function (≥90 ml/min; n = 381), mild renal impairment (60-89 ml/min; n = 139), moderate renal impairment (30-59 ml/min; n = 64), severe renal impairment (15-29 ml/min; n = 5), and end-stage renal disease (<15 ml/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. CONCLUSIONS: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.
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