Sunitinib
|
Better Known as: Sutent
- Marketed By: Pfizer
- Major Indication: Renal Cell Carcinoma & Gastrointestinal Cancer
- Drug Class: Receptor Tyrosine Kinase (Including VEGFR & PDGFR) & KIT Cytokine Receptor Inhibitor
- Date of FDA Approval (Patent Expiration): 2006 (2020)
- 2009 Sales: $964 Million [1]
- Importance: Currently among the most effective cancer treatments available. Sunitinib is the first treatment for renal cell carcinoma to demonstrate an overall survival of longer than two years. Has very impressive results with gastrointestinal stromal tumors. It was the first cancer drug to be approved simultaneously for two different indications. Controversial due to its high cost of $38,000 per year.
- See Pharmaceutical Drugs for more information about other drugs and disorders.
Mechanism of Action
Sunitinib inhibits cellular signaling by targeting several different receptor tyrosine kinases (RTKs) including receptors for platelet-derived growth factor (PDGFRs) and vascular endothelial growth factor receptors (VEGFR). PDGFR and VEGFR play crucial roles in both tumor angiogenesis and cellular proliferation. Inhibition of PDGFR and VEGFR results in reduced tumor vascularization and cancer cell death. Sunitinib is also an inhibitor of KIT, a cytokine receptor inhibitor. KIT binds to stem cell factor, upon which KIT dimerizes and transmit second messenger signals ultimately resulting in cell survival and proliferation. Mutations of the KIT gene are associated with most gastrointestinal stromal tumors.[2]
Pharmacokinetics
| VEGFR Inhibitor Pharmacokinetics[3][4][5][6][7] | |||||
|---|---|---|---|---|---|
| Parameter | Sunitinib (Sutent) | Sorafenib (Nexavar) | |||
| Tmax (hr) | 8 | 8.3 | |||
| Cmax (ng/ml) | 24.6 | 460 | |||
| Bioavailability (%) | Variable | 29-49 | |||
| Protein Binding (%) | 95 | 99 | |||
| T1/2 (hr) | 83 | 29 | |||
| AUC (ng/ml/hr) | 1921 | 11040 | |||
| Dosage (mg) | 50 | 50 | |||
| Metabolism | Hepatic (CYP3A4) | Hepatic (CYP3A4) | |||
References
- ↑ http://www.inpharm.com/news/101125/renal-cell-carcinoma-market-votrient-sutent
- ↑ Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors. Cancer Genet Cytogenet. 2002 May;135(1):1-22. PMID:12072198
- ↑ D. Smith et al. Br J Clin Pharmacol. 2009 April; 67(4): 421–426.
- ↑ R. Khosravan, et al. General Poster Session, Developmental Therapeutics: Cytotoxic Chemotherapy, J Clin Oncol 26: 2008 (May 20 suppl; abstr 2578)
- ↑ Lathia C, Lettieri J, Cihon F, Gallentine M, Radtke M, Sundaresan P. Lack of effect of ketoconazole-mediated CYP3A inhibition on sorafenib clinical pharmacokinetics. Cancer Chemother Pharmacol. 2006 May;57(5):685-92. Epub 2005 Aug 25. PMID:16133532 doi:10.1007/s00280-005-0068-6
- ↑ Brendel E, Ludwig M, Lathia C, Robert C, Ropert S, Soria JC, Armand JP. Pharmacokinetic results of a phase I trial of sorafenib in combination with dacarbazine in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2010 Sep 7. PMID:20821331 doi:10.1007/s00280-010-1423-9
- ↑ Boven E, Massard C, Armand JP, Tillier C, Hartog V, Brega NM, Countouriotis AM, Ruiz-Garcia A, Soria JC. A phase I, dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours. Br J Cancer. 2010 Sep 28;103(7):993-1000. Epub 2010 Aug 17. PMID:20717111 doi:10.1038/sj.bjc.6605852