Home Cancer Drugs Sorafenib-Mechanism of Action, Indications, Dose, Side Effects
- Kinase inhibitor that decreases tumor cell proliferation.
- Inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß)
- Phase 3 placebo controlled trial (TARGET trial)
- Advanced RCC who had received one prior systemic therapy
Unresectable Liver Cancer (Hepatocellular Carcinoma)
- SHARP trial – Advanced HCC and demonstrated a survival advantage for sorafenib versus placebo.
|Time to progression
|Risk of death
||Decreased by 31%
Locally recurrent or metastatic, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment.
- Placebo controlled trial (DECISION trial)
- Locally recurrent or metastatic differentiated thyroid cancer refractory to radioactive iodine treatment
Mechanism of Action
- Inhibits multiple intracellular cytoplasmic (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-β).
- Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis.
- Rapidly absorbed after oral dose (oral bioavailability is 40-50%)
- Peak plasma level – within 2-7 hrs
- Metabolized in liver by CYP3A4 and by glucuronidation by UGT1A9.
- Elimination t1/2 is 25-50hrs
- Steady state plasma concentration achieved in 7 days
- 77% of drug excreted in feces and 19% in urine.
Dose and Administration
- The recommended daily dose of sorafenib is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal).
- Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs
- Elevated lipase
- Dose modification is recommended depending on the grade of cutaneous toxicity.
- No dose adjustment is necessary for patients with mild or moderate hepatic impairment and renal impairment.
- The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment.
- Cardiovascular: hypertensive crisis, myocardial ischemia and/or infarction, congestive heart failure
- Dermatologic: erythema, exfoliative dermatitis, acne, flushing. folliculitis, eczema, erythema multiforme
- Digestive: increased lipase, increased amylase, mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, pancreatitis, gastrointestinal reflux, gastritis, gastrointestinal perforations
- General Disorders: hemorrhage (including gastrointestinal & respiratory tract and cerebral hemorrhage), asthenia, pain (including mouth, bone, and tumor pain) decreased appetite, influenza-like illness, pyrexia, infection
- Hematologic: leukopenia, lymphopenia, anemia, neutropenia, thrombocytopenia, INR abnormal
- Hypersensitivity: hypersensitivity reactions (including skin reactions and urticaria)
- Metabolic and Nutritional: hypophosphatemia, transient increases in transaminases
- Musculoskeletal: arthralgia, myalgia
- Nervous System and Psychiatric: depression, tinnitus, reversible posterior leukoencephalopathy
- Reproductive: erectile dysfunction, gynecomastia
- Respiratory: hoarseness, rhinorrhea
- UGT1A1 and UGT1A9 Substrates: Caution is recommended with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways .
- Docetaxel: Concomitant use of docetaxel, resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax.
- Doxorubicin: Concomitant treatment resulted in a 21% increase in the AUC of doxorubicin.
- Fluorouracil: Both increases (21%-47%) and decreases (10%) in the AUC of fluorouracil were observed .
- CYP2B6 and CYP2C8 Substrates: Sorafenib inhibits CYP2B6 and CYP2C8 .
- CYP3A4 Inducers: Inducers of CYP3A4 activity may increase metabolism of sorafenib and thus decrease sorafenib concentrations.
- Risk of Cardiac Ischemia and/or Infarction- Temporary or permanent discontinuation of drug should be considered in patients who develop cardiac ischemia and/or infarction.
- Risk of Hemorrhage – If any bleeding necessitates medical intervention, permanent discontinuation should be considered.
- Risk of Hypertension – Blood pressure should be monitored weekly during the first 6 weeks, thereafter monitored and treated, if required, in accordance with standard medical practice
- Risk of Dermatologic Toxicities – Hand-foot skin reaction and rash represent the most common adverse reactions. Rash and hand-foot skin reaction usually appear during the first six weeks . Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of drug, or in severe or persistent cases, permanent discontinuation of drug.
- Warfarin Co-administration – Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin. Patients taking concomitant warfarin should be monitored regularly.
- Wound Healing Complications – No formal studies of the effect of sorafinib on wound healing have been conducted. Temporary interruption of therapy is recommended in patients undergoing major surgical procedures. The decision to resume therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing.