Bosutinib

Bosutinib (rINN/USAN; codenamed SKI-606, marketed under the trade name Bosulif) is a small molecule BCR-ABL and src tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia.

Bosutinib
Clinical data
Trade namesBosulif
License data
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Protein binding94–96%
    MetabolismBy CYP3A4, to inactive metabolites
    Elimination half-life22.5±1.7 hours
    ExcretionFoecal (91.3%) and renal (3%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard100.149.122
    Chemical and physical data
    FormulaC26H29Cl2N5O3
    Molar mass530.45 g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Originally synthesized by Wyeth, it is being developed by Pfizer.

    Mechanism

    It is an ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an additional inhibitory effect on SRc family kinases (including Src, Lyn and Hck).[1][2] It has also shown activity against the receptors for platelet derived growth factor and vascular endothelial growth factor.[3] 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.[1]

    Bosutinib is metabolized through CYP3A4.

    Medical uses

    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.[4][5][6][7]

    Adverse effects

    Very common (>10% frequency): [8]

    • Diarrhoea (~82%)
    • Arterial occlusive events such as stroke or heart attack (44% in patients with chronic myeloid leukemia).[9]
    • Nausea
    • Myelosuppression[Note 1]
    • Vomiting (~37%)
    • Abdominal pain
    • Raised ALT
    • Raised AST
    • Rash
    • Arthralgia (joint pain)
    • Fever
    • Oedema
    • Fatigue
    • Cough
    • Headache
    • Reduced appetite
    • Respiratory tract infection[Note 2]

    Common (1-10% frequency):

    • Drug hypersensitivity
    • Dehydration
    • Hyperkalaemia (high blood potassium)
    • Hypophosphataemia (low blood phosphate)
    • Dizziness
    • 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
    • Acne
    • Itchiness
    • Hives
    • Myalgia (muscle aches)
    • Back pain
    • Kidney failure
    • Chest pain
    • Pain
    • Muscle weakness
    • Increased lipase
    • Increased blood creatinine
    • Increased blood amylase level
    • Elevated blood creatine phosphokinase

    Uncommon (0.1-1% frequency):

    Contraindications

    Bosutinib has two known absolute contraindications, which are: known hypersensitivity to bosutinib and liver impairment.[8][10]

    = Interactions

    =

    Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4.[1] Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib.[1] Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib.[1] 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.[1]

    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.[10] Mutagenic and clastogenic effects were not detected in vitro.[10]

    Quality issues

    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.[11]

    Notes
    1. Including thrombocytopaenia, anaemia, neutropaenia and leucopaenia.
    2. Including: pneumonia, bronchitis and influenza
    gollark: Also people just not caring about truth for some reason. A mere 1.8ish hours ago someone was telling me about why they believed in astrology.
    gollark: That seems like more of an argument for mitigating the harms of some service things than just banning somewhat harmful ones entirely.
    gollark: AAAAAAAAAA MORE "OR SOMETHING"
    gollark: I'm not sure about "fundamentally", but common cultural values consider it more intimate than just, I don't know, retailing or waiter-ing.
    gollark: Okay, that's better. Really need to avoid that.

    See also
    • Discovery and development of Bcr-Abl tyrosine kinase inhibitors

    References
    1. "Bosulif (bosutinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 3 January 2014.
    2. Daud AI, Krishnamurthi SS, Saleh MN, Gitlitz BJ, Borad MJ, Gold PJ, et al. (February 2012). "Phase I study of bosutinib, a src/abl tyrosine kinase inhibitor, administered to patients with advanced solid tumors". Clinical Cancer Research. 18 (4): 1092–100. doi:10.1158/1078-0432.CCR-11-2378. PMID 22179664.
    3. "Bosutinib". livertox.nih.gov.
    4. Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, et al. (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". Blood. 118 (17): 4567–76. doi:10.1182/blood-2011-05-355594. PMC 4916618. PMID 21865346.
    5. Cortes JE, Kim DW, Kantarjian HM, Brümmendorf TH, Dyagil I, Griskevicius L, et al. (October 2012). "Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial". Journal of Clinical Oncology. 30 (28): 3486–92. doi:10.1200/JCO.2011.38.7522. PMC 4979199. PMID 22949154.
    6. "Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia". 5 Sep 2012.
    7. "Bosulif : EPAR - Product Information" (PDF). European Medicines Agency. Pfitzer Ltd. 9 April 2013. Retrieved 3 January 2014.
    8. "Bosulif 100mg and 500mg Tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfitzer Limited. 7 June 2013. Retrieved 3 January 2014.
    9. Caocci G, Mulas O, Bonifacio M, Abruzzese E, Galimberti S, Orlandi EM, et al. (August 2019). "Recurrent arterial occlusive events in patients with chronic myeloid leukemia treated with second- and third-generation tyrosine kinase inhibitors and role of secondary prevention". International Journal of Cardiology. 288: 124–127. doi:10.1016/j.ijcard.2019.04.051. PMID 31029498.
    10. "BOSULIF (bosutinib monohydrate) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]". DailyMed. Pfitzer Inc. September 2013. Retrieved 3 January 2014.
    11. Derek Lowe, In The Pipeline (blog), "Bosutinib: Don't Believe the Label!"
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