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.
  
  
  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.
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
authors.affiliation: New York Medical College, Valhalla, NY, USA.
authors.forename: Janice P
authors.initials: JP
authors.lastname: Dutcher
authors.affiliation: University of New Mexico Cancer Center, Albuquerque, NM, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rixe
authors.affiliation: University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI, USA.
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.affiliation: Department of Medicine, University of Chicago, Chicago, IL, USA.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: Jamal
authors.initials: J
authors.lastname: Tarazi
authors.affiliation: Pfizer Oncology, San Diego, CA, USA.
authors.forename: May
authors.initials: M
authors.lastname: Garrett
authors.affiliation: Pfizer Oncology, San Diego, CA, USA. yazdi.pithavala@pfizer.com.|Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 92121, USA. yazdi.pithavala@pfizer.com.
authors.forename: Yazdi K
authors.initials: YK
authors.lastname: Pithavala
mesh_terms: D000077784:Axitinib; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016032:Randomized Controlled Trials as Topic
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D000077784:Axitinib