PMID- 26400730
OWN - NLM
STAT- MEDLINE
DCOM- 20170227
LR  - 20181202
IS  - 1776-260X (Electronic)
IS  - 1776-2596 (Print)
IS  - 1776-2596 (Linking)
VI  - 11
IP  - 2
DP  - 2016 Apr
TI  - Effect of Renal Impairment on the Pharmacokinetics and Safety of Axitinib.
PG  - 229-34
LID - 10.1007/s11523-015-0389-2 [doi]
AB  - 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.
FAU - Chen, Ying
AU  - Chen Y
AD  - Pfizer Oncology, San Diego, CA, USA.
FAU - Rini, Brian I
AU  - Rini BI
AD  - Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
FAU - Motzer, Robert J
AU  - Motzer RJ
AD  - Memorial Sloan Kettering Cancer Center, New York, NY, USA.
FAU - Dutcher, Janice P
AU  - Dutcher JP
AD  - New York Medical College, Valhalla, NY, USA.
FAU - Rixe, Olivier
AU  - Rixe O
AD  - University of New Mexico Cancer Center, Albuquerque, NM, USA.
FAU - Wilding, George
AU  - Wilding G
AD  - University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI, USA.
FAU - Stadler, Walter M
AU  - Stadler WM
AD  - Department of Medicine, University of Chicago, Chicago, IL, USA.
FAU - Tarazi, Jamal
AU  - Tarazi J
AD  - Pfizer Oncology, San Diego, CA, USA.
FAU - Garrett, May
AU  - Garrett M
AD  - Pfizer Oncology, San Diego, CA, USA.
FAU - Pithavala, Yazdi K
AU  - Pithavala YK
AD  - Pfizer Oncology, San Diego, CA, USA. yazdi.pithavala@pfizer.com.
AD  - Clinical Pharmacology, Pfizer Inc, 10555 Science Center Drive, San Diego, CA, 
      92121, USA. yazdi.pithavala@pfizer.com.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - France
TA  - Target Oncol
JT  - Targeted oncology
JID - 101270595
RN  - 0 (Imidazoles)
RN  - 0 (Indazoles)
RN  - 0 (Protein Kinase Inhibitors)
RN  - C9LVQ0YUXG (Axitinib)
SB  - IM
MH  - Axitinib
MH  - Carcinoma, Renal Cell/drug therapy/*metabolism/physiopathology
MH  - Case-Control Studies
MH  - Clinical Trials, Phase II as Topic
MH  - Clinical Trials, Phase III as Topic
MH  - Humans
MH  - Imidazoles/administration & dosage/*adverse effects/*pharmacokinetics
MH  - Indazoles/administration & dosage/*adverse effects/*pharmacokinetics
MH  - Kidney/metabolism/*physiopathology
MH  - Kidney Neoplasms/drug therapy/*metabolism/physiopathology
MH  - Protein Kinase Inhibitors/administration & dosage/*adverse 
      effects/*pharmacokinetics
MH  - Randomized Controlled Trials as Topic
PMC - PMC5568082
MID - NIHMS896690
COIS- Compliance with Ethical Standards Olivier Rixe and George Wilding have no 
      conflicts of interest to disclose.
EDAT- 2015/09/25 06:00
MHDA- 2017/02/28 06:00
PMCR- 2017/08/23
CRDT- 2015/09/25 06:00
PHST- 2015/09/25 06:00 [entrez]
PHST- 2015/09/25 06:00 [pubmed]
PHST- 2017/02/28 06:00 [medline]
PHST- 2017/08/23 00:00 [pmc-release]
AID - 10.1007/s11523-015-0389-2 [pii]
AID - 10.1007/s11523-015-0389-2 [doi]
PST - ppublish
SO  - Target Oncol. 2016 Apr;11(2):229-34. doi: 10.1007/s11523-015-0389-2.