Sunitinib inhibits cellular signaling by targeting multiple RTKs. These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R). Sunitinib also inhibits KIT (CD117), the RTK that drives the majority of GISTs. In addition, sunitinib inhibits other RTKs including RET, CSF-1R, and flt3.
Mechanism of Action of Sunitinib
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.
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Sunitinib malate, an inhibitor of multiple receptor tyrosine kinases, is an antineoplastic agent. Receptor tyrosine kinases (RTKs) are involved in the initiation of various cascades of intracellular signaling events that lead to cell proliferation and/or influence processes critical to cell survival and tumor progression (eg, angiogenesis, metastasis, inhibition of apoptosis), based on the respective kinase. Although the exact mechanism of antineoplastic activity of sunitinib has not been fully elucidated, data from biochemical and cellular assays indicate that sunitinib may inhibit signal transduction pathways involving multiple receptors (ie, cell surface) tyrosine kinases, including platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR-1, VEGFR-2, VEGFR-3), stem cell factor receptor (ie, c-Kit), forms-like tyrosine kinase 3 (Flt-3), colony stimulating factor receptor type 1 (CSF-1R), and the glial cell line-derived neurotrophic factor receptor (RET). Sunitinib-induced inhibition of signal transduction pathways involving PDGFR-beta, VEGFR-2, and c-Kit has been confirmed in tumor xenografts expressing receptor tyrosine kinase targets in vivo. Sunitinib has been shown to inhibit the growth of tumor cells expressing dysregulated target receptor tyrosine kinases (ie, PDGFR, RET, c-Kit) in vitro; the drug also has been shown to inhibit PDGFR-beta- and VEGFR-2-dependent tumor angiogenesis in vivo.
Indications of Sunitinib
- Renal Cell Carcinoma
- Gastrointestinal Stromal Tumor
- Pancreatic Cancer
- Advanced Renal Cell Carcinoma
- Soft Tissue Sarcoma
- Thyroid Cancers
- Gastrointestinal stromal tumor
- Sutent is indicated for the treatment of unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST) in adults after a failure of imatinib treatment due to resistance or intolerance.
- Metastatic renal cell carcinoma
- Sutent is indicated for the treatment of advanced/metastatic renal cell carcinoma (MRCC) in adults.
- Pancreatic neuroendocrine tumors
- Sutent is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors with disease progression in adults.
- Experience with Sutent as first-line treatment is limited.
- Metastatic Pancreatic Neuroendocrine Tumors
- Refractory Gastrointestinal stromal tumor
- Unresectable, locally advanced Pancreatic Neuroendocrine Tumors
- For the treatment of advanced renal cell carcinoma as well as the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.
Contra Indication of Sunitinib
- Diabetes
- High cholesterol
- Low amount of magnesium in the blood
- Low amount of phosphate in the blood
- Low amount of calcium in the blood
- Low amount of sodium in the blood
- HThe high amount of potassium in the blood
- Low amount of potassium in the blood
- Anemia
- Decreased Blood Platelets
- Decreased Neutrophils a Type of White Blood Cell
- High blood pressure
- Very Rapid Heartbeat – Torsades de Pointes
- prolonged QT interval on EKG
- Abnormal EKG with QT changes from Birth
- Hardening of the arteries due to plaque buildup
- Liver problems
- High Amount of Bilirubin in the Blood
- High Blood Sugar
- Abnormal liver function tests
- Pregnancy
- A mother who is producing milk and breastfeeding
- Relapse of Hepatitis B Infection Symptoms
- Pancreatitis
- past history of complete removal of the stomach
Dosages of Sunitinib
Strengths: 12.5 mg; 25 mg; 37.5 mg; 50 mg
Renal Cell Carcinoma
- 50 mg orally once daily on a schedule of 4 weeks on treatment followed by 2 weeks off
Gastrointestinal Stromal Tumor
- 50 mg orally once daily on a schedule of 4 weeks on treatment followed by 2 weeks off
Pancreatic Cancer
- 37.5 mg orally once daily
Side Effects of Sunitinib
The most common
- chest pain
- certainly hair loss
- a headache
- joint painPain
- dizziness
- nausea and vomiting
- Severe stomach ache
- epigastric pain,
- diarrhoea,
- anorexia,
- flatulence,
- a headache,
- dizziness,
- fainting, fast or pounding heartbeats.
More common
- Fast or irregular heartbeat
- appetite loss
- changes in nails
- constipation
- fatigue
- fever
- Back pain
- dizziness
- a headache
- increased cough
- Acid or sour stomach
- decreased appetite
- Agitation
- chest congestion
- chest pain
- cold sweats
- confusion
- decreased sexual ability or desire
- stomach or abdominal cramps, gas, or pain
- trouble sleeping
Less common
- bleeding gums
- blood in the urine or stools
- chest pain
- diarrhea
- Burning, crawling, itching, numbness, prickling, “pins and needles“, or tingling feelings
- difficulty in moving
- muscle stiffness
- redness of the face, neck, arms and occasionally, upper chest
- lack or loss of strength
- muscle spasm
- difficult or labored breathing
- dry mouth
- a headache
- irritability
- lack or loss of strength
- loose stools
- loss of interest or pleasure
- muscle stiffness
- night sweats
- passing gas
- stomach discomfort, upset, or pain
- swollen joints
- trouble concentrating
- increased blood pressure
Drug Interactions of Sunitinib
Sunitinib may interact with following drugs, supplements & may change the efficacy of drugs
- alpha blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
- anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
- “azole” antifungal medications (e.g., fluconazole, itraconazole, ketoconazole)
- beta-blockers (e.g., atenolol, propranolol, metoprolol)
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- benzodiazepines (e.g., chlordiazepoxide, clonazepam, diazepam, lorazepam)
- calcium channel blockers (e.g., nifedipine, diltiazem, verapamil, amlodipine,
- carbamazepine
- chloroquine
- corticosteroids (e.g., dexamethasone, prednisone, methylprednisolone)
- cyclosporine
- dantrolene
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
- losartan
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- metronidazole
- mirtazapine
- montelukast
- norfloxacin
- ondansetron
- carbamazepine
- phenytoin
- progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
- proton pump inhibitors (PPIs; e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine,paroxetine, sertraline)
- sildenafil
- “statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- tadalafil
- tetracycline
- theophylline
- tolterodine
- tramadol
- other selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline)
- 5-HT3 antagonists (e.g., granisetron, ondansetron)
- tamsulosin
- tapentadol
- thiazide diuretics (e.g., hydrochlorothiazide, indapamide)
- tramadol
- tricyclic antidepressants (e.g., nortriptyline, amitriptyline, imipramine,
- other tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
- tetracycline
- tocilizumab
- vandetanib
- vemurafenib
- trimethoprim
- warfarin
Pregnancy & Lactation
FDA Pregnancy Category D
Pregnancy
This medication should not be used during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
It is not known if sunitinib passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. The safety and effectiveness of using this medication have not been established for children.
References
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