Effect of renal impairment on the pharmacokinetics and safety of axitinib Journal Article

Authors: Chen, Y.; Rini, B. I.; Motzer, R. J.; Dutcher, J. P.; Rixe, O.; Wilding, G.; Stadler, W. M.; Tarazi, J.; Garrett, M.; Pithavala, Y. K.
Article Title: Effect of renal impairment on the pharmacokinetics and safety of axitinib
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.
Keywords: metabolism; inhibitor; targeted therapies; cell carcinoma; efficacy; phase-ii; disease; ag-013736; antiangiogenesis; cancer
Journal Title: Targeted Oncology
Volume: 11
Issue: 2
ISSN: 1776-2596
Publisher: Springer  
Date Published: 2016-04-01
Start Page: 229
End Page: 234
Language: English
ACCESSION: WOS:000373695200010
DOI: 10.1007/s11523-015-0389-2
PUBMED: 26400730
PMCID: PMC5568082
Notes: Article -- Source: Wos
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MSK Authors
  1. Robert Motzer
    1075 Motzer