Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics.
OBJECTIVE
To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment.


METHODS
In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed. Changes in axitinib plasma exposures in subjects with mild or moderate hepatic impairment were predicted using computer simulations and used to guide initial dosing in the clinical study.


RESULTS
Axitinib exposure was similar in subjects with normal hepatic function and those with mild hepatic impairment, but approximately twofold higher in subjects with moderate hepatic impairment. Axitinib exposure weakly correlated with measures of hepatic function but was not affected by smoking status. Axitinib protein binding was similar in the three treatment groups. No significant treatment-related adverse events were reported.


CONCLUSIONS
Compared with subjects with normal hepatic function, moderate hepatic impairment increased axitinib exposure, suggesting that the oral clearance of axitinib is altered in these subjects. In addition, these data indicate a possible need for a dose reduction in subjects who develop moderate or worse hepatic impairment during axitinib treatment. A single 5-mg dose of axitinib was well tolerated in subjects with mild or moderate hepatic impairment.
Tortorici
Michael A
MA
Pfizer Oncology, San Diego, CA 92121, USA. michael.tortorici@pfizer.com
Toh
Melvin
M
Rahavendran
S V
SV
Labadie
Robert R
RR
Alvey
Christine W
CW
Marbury
Thomas
T
Fuentes
Ernesto
E
Green
Matthew
M
Ni
Grace
G
Hee
Brian
B
Pithavala
Yazdi K
YK
D000284:Administration, Oral; D000328:Adult; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077784:Axitinib; D016022:Case-Control Studies; D003198:Computer Simulation; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D007191:Indazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D012907:Smoking / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D000077784:Axitinib