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and its primary active metabolite were the major drug-related compounds identified in plasma, urine, and feces,<br />
representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were<br />
identified in urine and feces but generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to<br />
62 L/hr with an inter-patient variability of 40%.<br />
Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and<br />
its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. With repeated<br />
daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold.<br />
Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By<br />
Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL.<br />
No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with<br />
repeated daily administration or with repeated cycles in the dosing regimens tested.<br />
The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested,<br />
including patients with GIST and RCC.<br />
Pharmacokinetics in Special Populations<br />
Population pharmacokinetic analyses of demographic data indicate that there are no clinically relevant<br />
effects of age, body weight, creatinine clearance, race, gender, or ECOG score on the pharmacokinetics of<br />
SUTENT or the primary active metabolite.<br />
Pediatric Use: The pharmacokinetics of SUTENT have not been evaluated in pediatric patients.<br />
Renal Insufficiency: Sunitinib systemic exposure after a single dose of SUTENT was similar in subjects<br />
with severe renal impairment (CL cr 80<br />
mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was<br />
47% lower in subjects with ESRD on hemodialysis compared to subjects with normal renal function.<br />
Hepatic Insufficiency: Systemic exposures after a single dose of SUTENT were similar in subjects with mild<br />
exocrine (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment compared to subjects with<br />
normal hepatic function.<br />
12.4 Cardiac Electrophysiology<br />
See Warnings and Precautions (5.4).<br />
13 NONCLINICAL TOXICOLOGY<br />
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility<br />
The carcinogenic potential of sunitinib has been evaluated in rasH2 transgenic mice. Gastroduodenal<br />
carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background<br />
hemangiosarcomas have been observed at doses of ≥25 mg/kg/day (approximately 7 times the AUC in patients<br />
administered the RDD of 50 mg/day) following daily dose administration of 1- or 6-months duration. No<br />
proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Sunitinib did not cause genetic<br />
damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome<br />
aberration) and an in vivo rat bone marrow micronucleus test.<br />
Effects on the female reproductive system were identified in a 3-month repeat dose monkey study (2, 6, 12<br />
mg/kg/day), where ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (≥5.1 times<br />
the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2<br />
mg/kg/day (≥0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the<br />
uterine and ovarian effects were reproduced at 6 mg/kg/day in the 9-month monkey study (0.3, 1.5 and 6<br />
mg/kg/day administered daily for 28 days followed by a 14 day respite; the 6 mg/kg dose produced a mean<br />
AUC that was ≥0.8 times the AUC in patients administered the RDD). A no effect level was not identified in<br />
the 3 month study; 1.5 mg/kg/day represents a no effect level in monkeys administered sunitinib for 9 months.<br />
Although fertility was not affected in rats, SUTENT may impair fertility in humans. In female rats, no<br />
fertility effects were observed at doses of ≤5.0 mg/kg/day [(0.5, 1.5, 5.0 mg/kg/day) administered for 21 days<br />
up to gestational day 7; the 5.0 mg/kg dose produced an AUC that was ≥5 times the AUC in patients<br />
administered the RDD], however significant embryolethality was observed at the 5.0 mg/kg dose. No<br />
reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day) for 58 days prior to mating with<br />
untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration,
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