Nibinase Mechanism of Action

Pharmacology: Pharmacodynamics: Sunitinib inhibits multiple receptor tyrosine kinase (RTKs) that are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was identified as an inhibitor of platelet-derived growth factor receptors (PDGFR_α and PDGFR_β), 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 reported in biochemical and cellular assays. And inhibition of function has been reported 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 (PDGFR_β, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression, and/or inhibited in metastases in some reported experimental models of cancer. Sunitinib reported to demonstrate the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFR_β, and VEGFR2-dependent tumor angiogenesis in vivo.
Reported clinical studies: The clinical safety and efficacy of sunitinib has been reported in subjects with malignant GIST who were resistant to imatinib (i.e., those who experienced disease progression during or following treatment with imatinib); or intolerant to imatinib (i.e., those who experienced significant toxicity during treatment with imatinib that precluded further treatment); in subjects with metastatic renal cell carcinoma (MRCC); the adjuvant treatment of patients at high risk of the recurrence of RCC following nephrectomy; and in subjects with unresectable pNET.
Efficacy is based on time to tumor progression and an increase in survival in GIST.
Efficacy is based on progression-free survival (PFS) and objective response rates (ORR) for treatment-naive and cytokine-refractory MRCC, respectively, and on PFS for pNET.
Pharmacokinetics: The pharmacokinetics of sunitinib and sunitinib malate were reported in 135 healthy volunteers and 266 subjects with solld tumors.
Absorption: Maximum plasma concentration (C_max) are generally reported between 6-12 hours (T_max) following oral administration. Food has no effect on the bioavailability of sunitinib.
Distribution: Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no apparent concentration dependence in the range of 100-4,000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was large (2,230 L), indicating distribution into the tissues. In the dosing range of 25-100 mg, the area under the plasma concentration-time curve (AUC) and C_max increased proportionately with dose.
Metabolism: The calculated in vitro Ki values for all CYP isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) reported that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.
Reported in-vitro studies indicate that sunitinib neither induces nor inhibits major CYP enzymes, including CYP3A4.
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 comprise 23% to 37% of the total exposure.
Elimination: Excretion is primarily via feces (61%) with renal elimination of drug and metabolites 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 were not found in plasma. Total oral clearance (CL/F) ranged from 34-62 L/hr with an inter-patient variability of 40%. Following administration of a single dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active desethyl metabolite were approximately 40-60 hours and 80-110 hours, respectively.
Pharmacokinetics in special patient groups: Hepatic Insufficiency: Sunitinib and its primary metabolite are mainly metabolized by the liver. Systemic exposures after a single dose of sunitinib 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. Sunitinib was not reported in subjects with severe (Child-Pugh Class C) hepatic impairment.
Renal Insufficiency: Population pharmacokinetic analyses have reported that sunitinib pharmacokinetics were unaltered in subjects with calculated creatinine clearances in the range of 42-347 mL/min. Systemic exposures after a single dose of sunitinib were similar in subjects with severe renal impairment (CL_cr <30 mL/min) compared to subjects with normal renal function (CL_cr >80 mL/min). Although sunitinib and its primary metabolite were not eliminated through hemodialysis in subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to subjects with normal renal function.
Cardiac Electrophysiology: QT interval prolongation was reported in a Phase 1 trial with 24 evaluable subjects, aged 20-87 years, with advanced malignancies. At therapeutic plasma concentrations, the maximum QTcF mean change from baseline was 9.6 msec (90% CI upper limit of 15.1 msec). At approximately twice the therapeutic concentrations, the maximum QTcF mean change from baseline was 15.4 msec (90% CI upper limit of 22.4 msec). Moxifloxacin (400 mg) used as a positive control reported a 5.6 msec maximum mean QTcF change from baseline. No subjects reported an effect on the QTc interval greater than Grade 2 (CTCAE version 3.0). No patient reported with a cardiac arrhythmia.
Plasma Pharmacokinetics: Following administration of a single oral dose in healthy volunteers, the elimination half-lives of sunitinib and its primary active metabolite are approximately 40-60 hours, and 80-110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary active 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 are 62.9-101 ng/mL which are target concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result in tumor stasis/growth reduction in vivo. No significant changes in the pharmacokinetics of sunitinib or the primary, active metabolite were reported with repeated daily administration or with repeated cycles in the dosing regimens tested.
The pharmacokinetics were similar in all solid tumor populations tested and in healthy volunteers.
Population Pharmacokinetics: Reported population pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age, body weight, creatinine clearance, gender, race or ECOG score on the pharmacokinetics of sunitinib or the primary active metabolite.
Weight, performance status: Reported population pharmacokinetic analyses of demographic data indicate that no starting dose adjustments are necessary for weight or ECOG performance status.
Gender: Available reported data indicate that females could have about 30% lower apparent clearance (CL/F) of sunitinib than males: this difference, however, does not necessitate starting dose adjustments.
Toxicology: Preclinical safety data: In reported rat and monkey repeated dose toxicity studies up to 9-months duration, the primary target organ effects were identified in the gastrointestinal tract (emesis and diarrhea in monkeys); adrenal gland (cortical congestion and/or hemorrhage in rats and monkeys, with necrosis followed by fibrosis in rats); hemolymphopoietic system (bone marrow hypocellularity, and lymphoid depletion of thymus, spleen, and lymph node); exocrine pancreas (acinar cell degranulation with single-cell necrosis); salivary gland (acinar hypertrophy); bone joint (growth plate thickening); uterus (atrophy); and ovaries (decreased follicular development). All findings occurred at clinically relevant sunitinib plasma exposure levels. Additional effects, reported in other studies included: QTc interval prolongation, LVEF reduction, and testicular tubular atrophy, increased mesangial matrix in kidney, hemorrhage in GI tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in the uterus (endometrial atrophy) and bone growth plate (physeal thickening or dysplasia of cartilage) are thought to be related to the pharmacological action of sunitinib. Most of these findings were reversible after 2 to 6 weeks without treatment.
Genotoxicity: The genotoxicity potential of sunitinib was reported in vitro and in vivo. Sunitinib was not mutagenic in bacteria using metabolic activation provided by rat liver. Sunitinib did not induce structural chromosome aberrations in human peripheral blood lymphocyte cells in vitro. Polyploidy (numerical chromosome aberrations) was reported in human peripheral blood lymphocytes in vitro, both in the presence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrow in vivo. The major active metabolite was not reported for genetic toxicity potential.
Carcinogenicity: Although definitive carcinogenicity studies with sunitinib have not been reported, in a 1-month, oral gavage dose-range finding study (0, 10, 25, 75, or 200 mg/kg/day) with continuous daily dosing in rasH2 transgenic mice, carcinoma and hyperplasia of Brunner's glands of the duodenum were reported at the highest dose (200 mg/kg/day) tested.
A 6-month, oral gavage carcinogenicity study (0, 8, 25, or 75 [reduced to 50] mg/kg/day), with daily dosing was conducted in rasH2 transgenic mice. Gastroduodenal carcinomas, an increased incidence of background hemangiosarcomas, and/or gastric mucosal hyperplasia were reported at doses of ≥25 mg/kg/day following 1- or 6-months duration (≥7.3 times the AUC in subjects administered the RDD).
In a 2-year rat carcinogenicity study (0, 0.33, 1, or 3 mg/kg/day), administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in increases in the incidence of pheochromocytomas and hyperplasia in the adrenal medulla of male rats given 3 mg/kg/day following >1 year of dosing (≥7.8 times the AUC in subjects administered the RDD). Brunner's glands carcinoma occurred in the duodenum at ≥1 mg/kg/day in females and at 3 mg/kg/day in males, and mucous cell hyperplasia was evident in the glandular stomach at 3 mg/kg/day in males, which occurred at ≥0.9, 7.8 and 7.8 times the AUC in subjects administered the RDD, respectively. The relevance to humans of the neoplastic findings reported in the mouse (rasH2 transgenic) and rat carcinogenicity studies with sunitinib treatment is unclear.
Reproductive and developmental toxicity: No effects on fertility were reported in male rats doses for 58 days prior to mating with untreated females. No reproductive effects were reported in female rats treated for 14 days prior to mating with untreated males, at doses resulting in systemic exposures approximately 5 times the systemic exposure in humans. However, in repeated-dose toxicity studies reported in rats and monkeys, effects on female fertility were reported in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in the uterus and decreased uterine and ovarian weights at clinically relevant systemic exposure levels. Moreover, in repeat-dose toxicity studies reported in rats, effects on male fertility were reported in the form of tubular atrophy in the testes, reduction of spermatozoa in epididymides and colloid depletion in prostate and seminal vesicles at plasma exposure levels 25 times the systemic exposure in humans. Not all the effects reported in male rats were reversible at the end of the recovery period (6 weeks).
In rats, treatment-related embryo-fetal mortality was evident as significant reductions in the number of live fetuses, increased numbers of resorptions (early and total), corresponding increased post-implantation loss, and total litter loss in 8 of 28 pregnant females at plasma exposure levels 5.5 times the systemic exposure in humans. In rabbits, reductions in gravid uterine weights and number of live fetuses were due to increases in the number of resorptions (early and total), increases in post-implantation loss, and complete litter loss in 4 of 6 pregnant females at plasma exposure levels 3 times the systemic exposure in humans.
Sunitinib treatment in rats during organogenesis resulted in developmental effects at ≥5 mg/kg/day consisting of increased incidence of fetal skeletal malformations, predominantly characterized as retarded ossification of thoracic/lumbar vertebrae. Developmental effects in rats occurred at plasma exposure levels 6 times the systemic exposure in humans. In rabbits, developmental effects consisted of increased incidence of cleft lip at plasma exposure levels approximately equal to that reported in clinic, and cleft palate at plasma exposure levels 2.7 times the systemic exposure in humans.
A definitive rabbit embryo-fetal development toxicity study was not reported as embryo-fetal effects were clearly demonstrated in the rat and reported in the preliminary study reported in rabbits.