Sunitinib Malate 37.5 mg Capsule, 28-count — NDC 0378-6681-28 (Billing 00378-6681-28)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 .

12.2Pharmacodynamics Exposure-Response Relationship Based on population pharmacokinetic/pharmacodynamic analyses, there were relationships between changes in different pharmacodynamic endpoints (i.e., safety and efficacy endpoints) over time and sunitinib plasma exposures. Cardiac Electrophysiology Sunitinib malate capsules 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) ] .

12.3Pharmacokinetics The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors. Sunitinib AUC and C max 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 (T max ) ranged from 6 to 12 hours. Effect of Food The administration of a single dose of sunitinib malate capsules 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 sunitinib 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… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 .

12.3Pharmacokinetics The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in healthy subjects and in patients with solid tumors. Sunitinib AUC and C max 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 (T max ) ranged from 6 to 12 hours. Effect of Food The administration of a single dose of sunitinib malate capsules 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 sunitinib 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 sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite C max and AUC 0-inf by 49% and 51%, respectively, in healthy subjects.

Effect of Strong CYP3A4 Inducers on Sunitinib Co-administration of a single sunitinib malate capsule dose with rifampin (strong CYP3A4 i… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Exposure-Response Relationship Based on population pharmacokinetic/pharmacodynamic analyses, there were relationships between changes in different pharmacodynamic endpoints (i.e., safety and efficacy endpoints) over time and sunitinib plasma exposures. Cardiac Electrophysiology Sunitinib malate capsules 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) ] .

Clinical Studies Effect of Strong CYP3A4 Inhibitors on Sunitinib Co-administration of a single sunitinib malate capsule dose with ketoconazole (strong CYP3A4 inhibitor) increased the combined sunitinib and its active metabolite C max and AUC 0-inf by 49% and 51%, respectively, in healthy subjects. Effect of Strong CYP3A4 Inducers on Sunitinib Co-administration of a single sunitinib malate capsule dose with rifampin (strong CYP3A4 inducer) reduced the combined sunitinib and its active metabolite C max and AUC 0-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.

14 CLINICAL STUDIES

14.1Gastrointestinal Stromal Tumor Study 1 Study 1 (NCT#00075218) was a 2-arm, international, randomized, double-blind, placebo-controlled trial of sunitinib malate capsules in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The objective was to compare time-to-tumor progression (TTP) in patients receiving sunitinib malate capsules plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS).

Patients were randomized (2:1) to receive either 50 mg sunitinib malate capsules or placebo orally, once daily, on Schedule 4/2 until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label sunitinib malate capsules and patients randomized to sunitinib malate capsules were permitted to continue treatment per investigator judgment.

At the time of a prespecified interim analysis, the intent-to-treat (ITT) population included 312 patients. Two hundred seven (207) patients were randomized to the sunitinib malate capsules arm and 105 patients were randomized to the placebo arm. Demographics were comparable between the sunitinib malate capsules and placebo groups with regard to age (69% versus 72% < 65 years for sunitinib malate capsules versus placebo, respectively), sex (male: 64% versus 61%), race (White: 88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and performance status (ECOG 0: 44% versus 46%, ECOG 1: 55% versus 52%, and ECOG 2: 1% versus 2%).

Prior treatment included surgery (94% versus 93%) and radiotherapy (8% versus 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% versus 4%), progression within 6 months of starting treatment (17% versus 16%), or progression beyond 6 months (78% versus 80%) balanced. The planned interim efficacy and safety analysis was performed after 149 TTP events had occurred.

There was a statistically significant advantage for sunitinib malate capsules over placebo in TTP, meeting the primary endpoint. Efficacy results are summarized in Table 10 and the Kaplan-Meier curve for TTP is shown in Figure 1. Table 10.

GIST Efficacy Results From Study 1 (Double-Blind Treatment Phase) Abbreviations: CI = confidence interval; GIST = gastrointestinal stromal tumor; HR = hazard ratio; N = number of patients; PR = partial response. Efficacy Parameter Sunitinib Malate Capsules (N = 207) Placebo (N = 105) p-value (log-rank test) HR (95% CI) Time-to-tumor progression Time from randomization to progression; deaths prior to documented progression were censored at time of last radiographic evaluation. [median, weeks (95% CI)] 27.3 (16.0, 32.1) 6.4 (4.4, 10.0) < 0.0001 A comparison is considered statistically significant if the p-value is < 0.00417 (O’Brien Fleming stopping boundary).

0.33(0.23, 0… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of sunitinib has been evaluated in 2 species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice, gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at sunitinib daily doses of ≥ 25 mg/kg/day in studies of 1 or 6 months duration.

No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day [approximately 0.9 times the combined AUC (combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg]. At the high dose of 3 mg/kg/day (approximately 8 times the combined AUC in patients administered the RDD of 50 mg), the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal gland.

Sunitinib did not cause genetic damage when tested in in vitro assays [bacterial mutation (Ames test), human lymphocyte chromosome aberration] and an in vivo rat bone marrow micronucleus test. In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5, 1.5, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating. Preimplantation loss was observed in females administered 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg).

No adverse effects on fertility were observed at doses ≤ 1.5 mg/kg/day (approximately equal to the combined AUC in patients administered the RDD of 50 mg). In addition, effects on the female reproductive system were identified in a 3-month oral repeat-dose monkey study (2, 6, 12 mg/kg/day). Ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg), while uterine changes (endometrial atrophy) were noted at ≥ 2 mg/kg/day (approximately 0.4 times the combined AUC in patients administered the RDD of 50 mg).

With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day (approximately 0.8 times the combined AUC in patients administered the RDD of 50 mg) in a 9-month monkey study (0.3, 1.5, and 6 mg/kg/day administered daily for 28 days followed by a 14-day respite). In a male fertility study, no reproductive effects were observed in male rats dosed with 1, 3, or 10 mg/kg/day oral sunitinib 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 (approximately ≥ 26 times the combined AUC in patients administered the RDD of 50 mg).