Sunitinib-Mechanism of Action, Indications, Dose, Side Effects

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Sunitinib

Mechanism of Action

  • Sunitinib is a multi-targeting RTK inhibitor. Sunitinib inhibits receptor tyrosine kinases, including VEGF1, VEGF2, PDGFα, PDGF-β, KIT receptor, and FLT3 receptor.
  • Renal cell carcinoma is believed to arise from a multistep process where the evolving cell acquires mutations within proto-oncogenes, tumor-suppressor genes, and other genes that regulate cell proliferation. The most common type of RCC is clear cell, representing 75% of all cases.
  • Clear cell RCC is associated with mutations in the von Hippel – Lindau (VHL) gene. Hypoxia-inducible factor 1 alfa is responsible for regulating gene expression during hypoxic stress. In hypoxic conditions, HIF-1α is translocated into the nucleus and binds with HIF-1β to form an active heterodimer HIF-1. Hypoxia-inducible factor-1 binds to other transcriptional cofactors that activate transcription of genes, including VEGF, EGFR, and PDGFR. The VHL gene product, in normostasis is a protein complex which ubiquitinates transcriptional factor hypoxia-inducible factor-1 alfa (HIF 1a) and prevents it from dimerizing with HIF-1β. VHL mutations result in decreased HIF-1α degradation, mimicking hypoxic conditions, which results in up-regulation of the genes that transcribe VEGF, EGFR, PDGFR and cause cellular proliferation, survival, and prevent apoptosis.

Indications

Gastrointestinal Stromal Tumor

Indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.

SUNITINIB PLACEBO
Median PFS 24.1m 6m
Time to progression 27.3m 6.4m

 

Advanced Renal Cell Carcinoma

Ph 3 trial SUNITINIB INF-α
PFS 11m 5m
OS 26.4m 21.8m
RR 31% 5%

Pharmacokinetics

  • 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..
  • Elimination is primarily via feces (61% in feces,16% renal)
  • With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold.
  • Steady-state concentrations are achieved within 10 to 14 days.

Dosage and Administration

  • 50 mg taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2).
  • To be used lifelong in the absence of disease progression
  • Taken with or without food
  • Do not take grapefruit during treatment
  • Available as 12.5, 25 and 50mg capsules

Dose Modification

  • Dose increase or reduction of 12.5 mg increments is recommended based on individual safety and tolerability.
  • Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma levels. A dose reduction for SUTENT to a minimum of 37.5 mg daily should be considered.
  • CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. A dose increase for SUTENT to a maximum of 87.5 mg daily should be considered

Side Effects

Gastrointestinal

  • Diarrhea
  • Mucositis/stomatitis
  • Constipation
  • pancreatitis

Cardiac

  • Hypertension
  • Cardiac failure

Dermatology

  • Skin discoloration
  • Rash
  • Hand-foot syndrome

Venous thromboembolic episodes

Neurology

  • Altered taste
  • Reversible Posterior Leukoencephalopathy Syndrome

Musculoskeletal

  • Myalgia/limb pain

Metabolism/Nutrition

  • Anorexia
  • Asthenia

Endocrine

  • Hypothyroidism
  • Adrenal insufficiency

Precautions

Left Ventricular Dysfunction

  • In symptomatic congestive heart failure (CHF), discontinuation of SUNITINIB is recommended.
  • SUNITINIB should be interrupted and/or dose reduced in patients without clinical evidence of CHF but with an ejection fraction < 50% and > 20% below baseline.
  • Baseline and periodic evaluations of LVEF should also be considered .
  • In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

QT Interval Prolongation and Torsades de Pointes

  • SUNITINIB has been shown to prolong the QT interval in a dose dependent manner in < 0.1% of patients.
  • SUNITINIB should be used with caution in patients who are taking antiarrhythmics, those with a history of QT interval prolongation, or with relevant pre-existing cardiac disease, bradycardia, or electrolyte
  • Periodic monitoring with electrocardiograms and electrolytes .

Hypertension

  • Patients should be monitored for hypertension
  • In cases of severe hypertension, temporary suspension of drug is recommended until hypertension is controlled.

Hemorrhagic Events

  • Epistaxis was the most common . Less common bleeding events include rectal, gingival, upper gastrointestinal, genital, and wound bleeding.
  • Tumor-related hemorrhage has been observed and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage.
  • Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred rarely in patients with intra- abdominal malignancies

Hypothyroidism

  • Baseline thyroid function is recommended before start of sunitinib
  • All patients should be observed closely for signs and symptoms of hypothyroidism .
  • Patients with signs or symptoms suggestive of hypothyroidism should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.

Adrenal Function

  • Monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection.

Laboratory Tests

  • CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment.

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