Sutent
Sutent
Generic Name
Sutent
Mechanism
- Potent, orally available inhibitor of multiple receptor tyrosine kinases (RTKs).
- Targets include:
- Vascular endothelial growth factor receptors (VEGFR‑1, 2, 3) – blocks angiogenesis.
- Platelet‑derived growth factor receptors (PDGFR‑α, β) – inhibits pericyte recruitment and vessel maturation.
- C‑Kit, Flt‑3, and RET – important in GIST and other neoplasms.
- Competitive, ATP‑mimetic binding to the kinase domain → prevents phosphorylation of downstream signaling (MAPK/ERK, PI3K/AKT).
- Results in cell cycle arrest, apoptosis, and reduced tumor vasculature.
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Pharmacokinetics
| Parameter | Typical Value |
| Absorption | Rapid; peak plasma concentrations at ~5–12 h after dosing, high oral bioavailability. |
| Distribution | Extensive; large volume of distribution; strong tissue binding (esp. liver, kidneys, skin). |
| Metabolism | Primarily hepatic via CYP3A4 and CYP2C19; N‑demethylation → active metabolites (mostly inactive). |
| Elimination | Mainly biliary excretion; half‑life ≈ 40 h (dose‑dependent). |
| Drug interactions | Highly susceptible to CYP3A4 inhibitors/inducers; concomitant use with high‑dose *steroids* or *dexamethasone* potentiates toxicity; avoid strong CYP3A4 substitutes (ketoconazole, ritonavir). |
| Special populations |
• Renal impairment: dose adjustment not required.
• Hepatic impairment: reduce starting dose.
• Pregnancy: Category D; avoid. |
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Indications
- Advanced/metastatic RCC (clear cell) – first‑line and second‑line.
- Resistant or progressive GIST – after failure of imatinib.
- Pancreatic neuroendocrine tumor (PanNET) – progressive, symptomatic.
- Adjuvant RCC (in selected patients with high risk of recurrence).
- Breast cancer – investigational (post‑marketing trial).
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Contraindications
| Contraindication / Warning | Key Points |
| Severe uncontrolled hypertension | Must be controlled before initiation. |
| Active bleeding / coagulopathy | High risk of hemorrhagic complications. |
| Cardiovascular disease | Screening for CHF; monitor LVEF. |
| Recent myocardial infarction (≤6 mo) | Avoid. |
| Pregnancy/Breastfeeding | Crippling teratogenicity; contraindicated. |
| Known hypersensitivity to sunitinib | Avoid. |
| Severe hepatic impairment (Child–Pugh B/C) | Dose 50 mg → 37.5 mg; avoid in C. |
| Concurrent potent CYP3A4 inhibitors | Contraindicated; adjust dose. |
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Dosing
- Standard regimen: 50 mg orally once daily, 4 weeks on / 2 weeks off (28‑day cycle).
- Alternate schedule: 37.5 mg daily, 4 weeks on / 1 week off (for intolerance).
- Administration: Take with or without food; whole capsule; avoid crushing.
- Adjustments:
- Hepatic impairment – reduce dose to 37.5 mg or 25 mg depending on B1/B2.
- Renal impairment – same dose as normal.
- Rescue therapy: Hold dose with ≥grade 3 toxicity; resume at 80 % dose after recovery to grade ≤2.
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Adverse Effects
| Category | Examples |
| Erythro‑delivery | Hand‑foot skin reaction, mucositis, fatigue, rash. |
| Hematologic | Anemia, leukopenia, thrombocytopenia (rare). |
| Cardiovascular | Hypertension, QT prolongation, congestive heart failure. |
| Gastro‑intestinal | Nausea, diarrhea, pneumonia. |
| Hepatic | Elevated AST/ALT, bilirubin (transient). |
| Dermatologic | Alopecia, hyperpigmentation, photosensitivity. |
| Other | Hypothyroidism (subclinical), interstitial lung disease (rare). |
• Serious:
• Hypertensive crisis, FFP.
• Cardiac dysfunction (≤10 % LVEF drop).
• Severe mucositis/hand‑foot syndrome requiring dose reduction.
• Interstitial lung disease – sudden onset dyspnea or cough.
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Monitoring
| Parameter | Frequency | Rationale |
| Blood pressure | Baseline, weekly for first month, then every 4 weeks | TKI‑induced hypertension. |
| CBC (with diff.) | Baseline, every 2–4 weeks | Detect cytopenias. |
| BMP/Serum electrolytes | Baseline, every 4 weeks | Monitor renal function, sodium. |
| Liver function tests | Baseline, every 4 weeks | Spot early hepatotoxicity. |
| Echocardiogram / LVEF | Baseline, every 3 months | Alterations in cardiac output. |
| Thyroid panel | Baseline, every 3 months | Subclinical hypothyroidism risk. |
| Skin exam | Baseline, every cycle | Identify hand‑foot syndrome. |
| Patient diary | Daily | Record dose adherence, adverse events. |
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Clinical Pearls
- Liver‐dependent metabolism → Avoid ketoconazole, ritonavir and induce (e.g., rifampin) categories; if unavoidable, dose‑reduce *sunitinib* to 25 mg daily.
- First‑cycle hypertension is predictive of efficacy; manage aggressively with ACE/ARB or calcium‑channel blockers early.
- Hand‑foot syndrome: Early moisturizers and dose modifications prevent progression; apply lidocaine‐soaked gauze for burning.
- QT prolongation requires baseline ECG and re‑check 2 weeks after dose escalation; avoid combining with strong QT‑prolonging drugs.
- Pharmacokinetic data indicate >95 % protein binding; plasma protein measurements are typically not justified.
- Breastfeeding: Drug is excreted into milk; contraindicated.
- Drug–drug interactions: Co‑administration with p‑methoxyacrylpyridine warfarin may increase bleeding; monitor INR.
- Immunologic adverse events (e.g., interstitial lung disease) are under‑recognized; any new respiratory symptoms within weeks of therapy warrant prompt evaluation.
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• Reference: Current prescribing information, NCCN guidelines (Version 2026), and peer‑reviewed pharmacology texts.