Sunitinib

Uses

Gastrointestinal Stromal Tumor (GIST): Sunitinib is used for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.

Advanced Renal Cell Carcinoma (RCC): Sunitinib is used for the treatment of advanced renal cell carcinoma.

Advanced Pancreatic Neuroendocrine Tumors (pNET): Sunitinib is used for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.

Sunitinib is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma, Soft Tissue Sarcoma (STS), Thyroid Cancers, Metastatic Pancreatic Neuroendocrine Tumors, Refractory Gastrointestinal stromal tumor, Unresectable, locally advanced Pancreatic Neuroendocrine Tumors

How Sunitinib works

Sunitinib is a small molecule that inhibits multiple 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 (PDGFRa and PDGFRb), 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.

Dosage

Sunitinib dosage

Recommended Dose For GIST And RCC:The recommended dose of Sunitinib for gastrointestinal stromal tumor (GIST) and advancedrenal cell carcinoma(RCC) is one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). Sunitinib may be taken with or without food.

Recommended Dose For pNET: The recommended dose of Sunitinib for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. Sunitinib may be taken with or without food.

Dose Modification: Dose interruption and/or dose modification in 12.5 mg increments or decrements is recommended based on individual safety and tolerability. The maximum dose administered in the Phase 3 pNET study was 50 mg daily.

Strong CYP3A4 inhibitors such as ketoconazole may increas e sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. A dose reduction for Sunitinib to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily should be considered if Sunitinib must be co-administered with a strong CYP3A4 inhibitor

CYP3A4 inducers such as rifampin may decreas e sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. A dose increase for Sunitinib to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily should be considered if Sunitinib must be co-administered with a CYP3A4 inducer. If dose is increased, the patient should be monitored carefully for toxicity

Side Effects

Fatigue, GI disorders, skin discoloration, rash, palmar-plantar erythrodysesthesia, dry skin, hair color changes, mucosal inflammation, asthenia, dysguesia, anorexia, HTN, neutropenia.

Toxicity

The maximally tolerated dose for rat, mouse, and dog when given orally is greater than 500 mg/kg. The maximally tolerated dose of a non-human primate is greater 1200 mg/kg.

Interaction

Increased plasma cone with strong CYP3A4 inhibitors (eg ketoconazole, ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice). Decreased plasma cone with strong CYP3A4 inducers [eg rifampin, dexamethasone, phenytoin, carbamazepine, phenobarb, St. John's wort (Hypericum perforatum)]. Anticoagulants eg warfarin, acenocoumarol (periodically monitor platelets, prothrombin time/INR & physical exam).

Food Interaction

• Avoid grapefruit products. Grapefruit may reduce the CYP3A4 metabolism of sunitinib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of sunitinib.
• Take with or without food.

[Moderate] GENERALLY AVOID: Consumption of grapefruit or grapefruit juice during sunitinib therapy may increase the plasma concentrations of sunitinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism by certain compounds present in grapefruit.

MANAGEMENT: Although clinical data are lacking, it may be advisable to avoid the consumption of large amounts of grapefruit or grapefruit juice during sunitinib therapy.

Sunitinib Hypertension interaction

[Moderate] The use of sunitinib has been associated with hypertension and it should be used with caution in patients with elevated blood pressure.

Therapy with sunitinib should be withheld in case of severe hypertension and appropriate measures should be taken to correct the blood pressure to acceptable readings.

Close monitoring of blood pressure is recommended.

Sunitinib Drug Interaction

Major: sotalolModerate: aripiprazole, amitriptyline, heparin, levofloxacinUnknown: rabeprazole, darbepoetin alfa, torsemide, fluorouracil topical, gemcitabine, imatinib, amlodipine, phenazopyridine, bioflavonoids, metoclopramide, vitamin a topical, bioflavonoids, ampicillin / sulbactam, cyanocobalamin, cholecalciferol

Sunitinib Disease Interaction

Major: liver diseaseModerate: lung toxicity, adrenal toxicity, cardiovascular Events, dermatologic toxicities, hemorrhagic events, hypertension, hypoglycemia, ONJ, proteinuria, QT prolongation, thyroid abnormality, Sunitinib – renal disease

Volume of Distribution

• 2230 L (apparent volume of distribution, Vd/F)

Elimination Route

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. Sunitinib may be taken with or without food. The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.

Half Life

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.

Clearance

• 34 - 62 L/h [Total oral clearance]

Elimination Route

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. 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.

Pregnancy & Breastfeeding use

Pregnancy Category D. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Contraindication

Hypersensitivity, Renal impairment

Acute Overdose

Treatment of overdose with Sunitinib should consist of general supportive measures. There is no specific antidote for overdosage with Sunitinib. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. Cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of Sunitinib, or without adverse reactions. A case of intentional overdose involving the ingestion of 1,500 mg of Sunitinib in an attempted suicide was reported without adverse reaction. In non-clinical studies mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m²) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

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