Mechanism of Action
Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs),
some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic
progression of cancer. Sunitinib was evaluated for its inhibitory activity against
a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived
growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor
receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like
tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and
the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition
of the activity of these RTKs has been demonstrated in biochemical and cellular
assays, and inhibition of function has been demonstrated in cell proliferation assays.
The primary metabolite exhibits similar potency compared to sunitinib in biochemical
and cellular assays.
Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in
tumor xenografts expressing RTK targets in vivo and demonstrated inhibition
of tumor growth or tumor regression and/or inhibited metastases in some experimental
models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor
cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and
to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.
Pharmacokinetics
The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135
healthy volunteers and in 266 patients with solid tumors.
Maximum plasma concentrations (Cmax) of sunitinib are
generally observed between 6 and 12 hours (Tmax) following
oral administration. Food has no effect on the bioavailability of sunitinib. SUTENT
may be taken with or without food.
Binding of sunitinib and its primary active metabolite to human plasma protein in
vitro was 95% and 90%, respectively, with no concentration dependence in
the range of 100 – 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib
was 2230 L. In the dosing range of 25 - 100 mg, the area under the plasma concentration-time
curve (AUC) and Cmax increase proportionately with dose.
Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce
its primary active metabolite, which is further metabolized by CYP3A4. The primary
active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily
via feces. In a human mass balance study of [14C]sunitinib,
61% of the dose was eliminated in feces, with renal elimination accounting for 16%
of the administered dose. Sunitinib and its primary active metabolite were the major
drug-related compounds identified in plasma, urine, and feces, representing 91.5%,
86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites
were identified in urine and feces but generally not found in plasma. Total oral
clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of
40%.
Following administration of a single oral dose in healthy volunteers, the terminal
half-lives of sunitinib and its primary active metabolite are approximately 40 to
60 hours and 80 to 110 hours, respectively. With repeated daily administration,
sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to
10-fold. Steady-state concentrations of sunitinib and its primary active metabolite
are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of
sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL. No significant
changes in the pharmacokinetics of sunitinib or the primary active metabolite were
observed with repeated daily administration or with repeated cycles in the dosing
regimens tested.
The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient
populations tested, including patients with GIST and MRCC.
Pharmacokinetics in Special Populations
Population pharmacokinetic analyses of demographic data indicate that there are
no clinically relevant effects of age, body weight, creatinine clearance, race,
gender, or ECOG score on the pharmacokinetics of SUTENT or the primary active metabolite.
Pediatric Use: The pharmacokinetics of SUTENT have not been evaluated in
pediatric patients.
Renal Insufficiency: No clinical studies of SUTENT were conducted in patients
with impaired renal function. Studies that were conducted excluded patients with
serum creatinine > 2.0 x ULN. Population pharmacokinetic analyses have shown
that sunitinib pharmacokinetics were unaltered in patients with calculated creatinine
clearances in the range of 42 –347 mL/min.
Hepatic Insufficiency: Systemic exposures after a single dose of SUTENT were
similar in subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class
B) hepatic impairment compared to subjects with normal hepatic function.
Cardiac Electrophysiology
See Warnings and Precautions.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Although definitive carcinogenicity studies with sunitinib have not been performed,
carcinoma and hyperplasia of the Brunner’s gland of the duodenum have been observed
at the highest dose tested in H2ras transgenic mice administered doses of 0, 10,
25, 75, or 200 mg/kg/day for 28 days. Sunitinib did not cause genetic damage when
tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte
chromosome aberration) and an in vivo rat bone marrow micronucleus test.
Effects on the female reproductive system were identified in a 3-month repeat dose
monkey study (2, 6, 12 mg/kg/day), where ovarian changes (decreased follicular development)
were noted at 12 mg/kg/day (approximately 5.1 times the AUC in patients administered
the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day
(approximately 0.4 times the AUC in patients administered the RDD). With the addition
of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day
in the 9-month monkey study (0.3, 1.5 and 6 mg/kg/day administered daily for 28
days followed by a 14 day respite; the 6 mg/kg dose produced a mean AUC that was
approximately 0.8 times the AUC in patients administered the RDD). A no effect level
was not identified in the 3 month study; 1.5 mg/kg/day represents a no effect level
in monkeys administered sunitinib for 9 months.
Although fertility was not affected in rats, SUTENT may impair fertility in humans.
In female rats, no 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 up to gestational day 7; the 5.0 mg/kg
dose produced an AUC that was approximately 5 times the AUC in patients administered
the RDD], however significant embryolethality was observed at the 5.0 mg/kg dose.
No reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day)
for 58 days prior to mating with untreated females. Fertility, copulation, conception
indices, and sperm evaluation (morphology, concentration, and motility) were unaffected
by sunitinib at doses ≤10 mg/kg/day (the 10 mg/kg/day dose produced a mean AUC that
was approximately 25.8 times the AUC in patients administered the RDD).