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SUTENT® (sunitinib malate) Clinical Pharmacology

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Cardiac Electrophysiology

SUTENT can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes [see Warnings and Precautions (5.3)].

12.3 Pharmacokinetics

The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors.

Sunitinib AUC and Cmax increase proportionately over a dose range of 25 mg to 100 mg (0.5 to 2 times the approved RDD of 50 mg). The pharmacokinetics were similar in healthy subjects and in patients with a solid tumor, including patients with GIST and RCC. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles. 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 63 to 101 ng/mL.

Absorption

Following oral administration of sunitinib, the time to maximum plasma concentration (Tmax) ranged from 6 to 12 hours.

Effect of Food

The administration of a single dose of SUTENT 50 mg with a high-fat, high-calorie meal (consisting of approximately 150 protein calories and 500 to 600 fat calories) in healthy subjects had no clinically significant effect on SUTENT or active metabolites exposure.

Distribution

The apparent volume of distribution (Vd/F) for sunitinib is 2230 L. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro is 95% and 90%, respectively, with no concentration dependence in the range of 100 to 4000 ng/mL.

Elimination

Following administration of a single oral dose in healthy subjects, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. Sunitinib total oral clearance (CL/F) ranged from 34 to 62 L/h with an interpatient variability of 40%.

Metabolism

Sunitinib is metabolized primarily by CYP3A4 to its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23% to 37% of the total exposure. After a radiolabeled dose, sunitinib and its active metabolite were the major compounds identified in plasma, accounting for 92% of radioactivity.

Excretion

After a radiolabeled dose of sunitinib, approximately 61% of the dose was recovered in feces and 16% in urine.

Sunitinib and its primary active metabolite were the major compounds identified in urine and feces, representing 86% and 74% of radioactivity, respectively.

Specific Populations

No clinically significant differences in the pharmacokinetics of sunitinib or the primary active metabolite were observed based on age (18 to 84 years), body weight (34 to 168 kg), race (White, Black, or Asian), sex, Eastern Cooperative Oncology Group (ECOG) score, mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.

Patients with Renal Impairment

No clinically significant differences in the pharmacokinetics of sunitinib or its active metabolite were predicted or observed in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis, compared to patients with normal renal function (CLcr >80 mL/min). Although sunitinib was not eliminated through hemodialysis, the sunitinib systemic exposure was 47% lower in patients with end stage renal disease (ESRD) on hemodialysis compared to patients with normal renal function.

Drug Interaction Studies

Clinical Studies

Effect of strong CYP3A4 inhibitors on sunitinib: Co-administration of a single SUTENT dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite Cmax and AUC0–inf by 49% and 51%, respectively, in healthy subjects.

Effect of strong CYP3A4 inducers on sunitinib: Co-administration of a single SUTENT dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite Cmax and AUC0–inf by 23% and 46%, respectively in healthy subjects.

In Vitro Studies

In vitro studies in human hepatocytes and microsomes indicated that sunitinib and the primary active metabolite do not induce CYP1A2, CYP2E1, and CYP3A4/5, or inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 at clinically relevant concentrations.

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