|Metabolism||By CYP3A4, to inactive metabolites|
|Biological half-life||22.5±1.7 hours|
|Excretion||Foecal (91.3%) and renal (3%)|
|Chemical and physical data|
|Molar mass||530.446 g/mol|
|3D model (JSmol)|
|(what is this?)|
Bosutinib (rINN/USAN; codenamed SKI-606, marketed under the trade name Bosulif) is a tyrosine kinase inhibitor undergoing research for use in the treatment of cancer. Originally synthesized by Wyeth, it is being developed by Pfizer.
Bosutinib received US FDA and EU European Medicines Agency approval on September 4, 2012 and 27 March 2013 respectively for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.
Adverse effects by incidence:
Very common (>10% frequency):
Common (1-10% frequency):
- Drug hypersensitivity
- Hyperkalaemia (high blood potassium)
- Hypophosphataemia (low blood phosphate)
- Dysgeusia (distorted sense of taste)
- Pericardial effusion
- Pleural effusion
- QT interval prolongation
- Shortness of breath
- Gastritis (stomach swelling)
- Hepatotoxicity (liver dysfunction/damage)
- Abnormal LFTs
- Elevated blood bilirubin levels
- GGT increased
- Myalgia (muscle aches)
- Back pain
- Kidney failure
- Chest pain
- Muscle weakness
- Increased lipase
- Increased blood creatinine
- Increased blood amylase level
- Elevated blood creatine phosphokinase
Uncommon (0.1-1% frequency):
Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4. Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib. Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib. It may also alter the metabolism and uptake (into the GIT by means of its P-gp inhibitory effects) of other drugs that are substrates for P-gp and CYP3A4.
Carcinogenicity and mutagenicity
Animal studies using up to three-times the clinical exposure (in terms of AUC) to bosutinib have failed to demonstrate any carcinogenic effects. Mutagenic and clastogenic effects were not detected in vitro.
Mechanism of action
It is an ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an additional inhibitory effect on SRc family kinases (including Src, Lyn and Hck). Bosutinib inhibited 16 of 18 imatinib-resistant forms of Bcr-Abl expressed in murine myeloid cell lines, but did not inhibit T315I and V299L mutant cells.
Some commercial stocks of bosutinib (from sources other than the Pfizer material used for clinical trials) have recently been found to have the incorrect chemical structure, calling the biological results obtained with them into doubt.
- Including thrombocytopaenia, anaemia, neutropaenia and leucopaenia.
- Including: pneumonia, bronchitis and influenza
- Puttini, M; Coluccia, AM; Boschelli, F; Cleris, L; Marchesi, E; Donella-Deana, A; Ahmed, S; Redaelli, S; Piazza, R; Magistroni, V; Andreoni, F; Scapozza, L; Formelli, F; Gambacorti-Passerini, C (Dec 2006). "In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells". Cancer Res. 66 (23): 11314–22. doi:10.1158/0008-5472.can-06-1199. PMID 17114238.
- Vultur A, Buettner R, Kowolik C, et al. (May 2008). "SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells". Mol. Cancer Ther. 7 (5): 1185–94. doi:10.1158/1535-7163.MCT-08-0126. PMC . PMID 18483306.
- Cortes, JE; Kantarjian, HM; Brümmendorf, TH; Kim, DW; Turkina, AG; Shen, ZX; Pasquini, R; Khoury, HJ; Arkin, S; Volkert, A; Besson, N; Abbas, R; Wang, J; Leip, E; Gambacorti-Passerini, C (October 2011). "Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib" (PDF). Blood. 118 (17): 4567–76. doi:10.1182/blood-2011-05-355594. PMC . PMID 21865346.
- Cortes, JE; Kim, DW; Kantarjian, HM; Brümmendorf, TH; Dyagil, I; Griskevicus, L; Malhotra, H; Powell, C; Gogat, K; Countouriotis, AM; Gambacorti-Passerini, C (October 2012). "Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial" (PDF). Journal of Clinical Oncology. 30 (28): 3486–3492. doi:10.1200/JCO.2011.38.7522. PMC . PMID 22949154.
- "Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia". 5 Sep 2012.
- "Bosulif : EPAR - Product Information" (PDF). European Medicines Agency. Pfitzer Ltd. 9 April 2013. Retrieved 3 January 2014.
- "Bosulif 100mg and 500mg Tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfitzer Limited. 7 June 2013. Retrieved 3 January 2014.
- "BOSULIF (bosutinib monohydrate) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]". DailyMed. Pfitzer Inc. September 2013. Retrieved 3 January 2014.
- "Bosulif (bosutinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 January 2014.
- Daud, AI; Krishnamurthi, SS; Saleh, MN; Gitlitz, BJ; Borad, MJ; Gold, PJ; Chiorean, EG; Springett, GM; Abbas, R; Agarwal, S; Bardy-Bouxin, N; Hsyu, PH; Leip, E; Turnbull, K; Zacharchuk, C; Messersmith, WA (February 2012). "Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors" (PDF). Clinical Cancer Research. 18 (4): 1092–100. doi:10.1158/1078-0432.CCR-11-2378. PMID 22179664.
- Derek Lowe, In The Pipeline (blog), "Bosutinib: Don't Believe the Label!"