Bosutinib

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Bosutinib
Bosutinib2DACS.svg
Bosutinib3Dan2.gif
Names
Trade namesBosulif
  • 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesChronic myelogenous leukemia (CML)[2]
Side effectsDiarrhea, rash, nausea, tiredness, liver problems, respiratory tract infection, fever, headache[2]
Routes of
use
By mouth
External links
AHFS/Drugs.comMonograph
US NLMBosutinib
Legal
License data
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
Pharmacokinetics
Protein binding94–96%
MetabolismBy CYP3A4, to inactive metabolites
Elimination half-life22.5±1.7 hours
ExcretionFoecal (91.3%) and renal (3%)
Chemical and physical data
FormulaC26H29Cl2N5O3
Molar mass530.45 g·mol−1
3D model (JSmol)
  • Clc1c(OC)cc(c(Cl)c1)Nc4c(C#N)cnc3cc(OCCCN2CCN(CC2)C)c(OC)cc34
  • InChI=1S/C26H29Cl2N5O3/c1-32-6-8-33(9-7-32)5-4-10-36-25-13-21-18(11-24(25)35-3)26(17(15-29)16-30-21)31-22-14-23(34-2)20(28)12-19(22)27/h11-14,16H,4-10H2,1-3H3,(H,30,31) checkY
  • Key:UBPYILGKFZZVDX-UHFFFAOYSA-N checkY

Bosutinib codenamed SKI-606, marketed under the trade name Bosulif, is a medication used to treat chronic myelogenous leukemia (CML).[2] Specifically it is used for cases that are Philadelphia chromosome positive.[2] It is taken by mouth.[2]

Common side effects include diarrhea, rash, nausea, tiredness, liver problems, respiratory tract infection, fever, and headache.[2] Other side effects may include bone marrow suppression, heart damage, swelling, and kidney problems.[2] Use in pregnancy may harm the baby.[2] It is a tyrosine kinase inhibitor that blocks BCR-ABL and src.[1]

Bosutinib was approved for medical use in the United States in 2012 and Europe in 2013.[2][1] In the United Kingdom 4 weeks of treatment costs the NHS about £3,400 as of 2021.[3] This amount in the United States is about 17,000 USD.[4]

Medical uses

Bosutinib received US FDA and EU European Medicines Agency approval in September 2012, and March 2013, respectively for the treatment of adults with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance, or intolerance to prior therapy.[5][6][7][8]

Dosage

It is generally started at a dose of 400 to 500 mg per day, though may be increased to 600 mg per day.[2]

Contraindications

Bosutinib has two known absolute contraindications, which are: known hypersensitivity to bosutinib and liver impairment.[9][10]

Interactions

Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4.[11] Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib.[11] Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib.[11] 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.[11]

Mechanism

WEE1 kinase domain in complex with bosutinib.

It is an ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an additional inhibitory effect on Src family kinases (including Src, Lyn and Hck).[11][12] It has also shown activity against the receptors for platelet derived growth factor and vascular endothelial growth factor.[13] 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.[11]

Bosutinib is metabolized through CYP3A4.

History

References

  1. 1.0 1.1 1.2 "Bosulif". Archived from the original on 14 November 2021. Retrieved 11 January 2022.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 2.9 "DailyMed - BOSULIF- bosutinib monohydrate tablet, film coated". dailymed.nlm.nih.gov. Archived from the original on 25 March 2021. Retrieved 11 January 2022.
  3. BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1015. ISBN 978-0857114105.
  4. "Bosulif Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 22 January 2021. Retrieved 11 January 2022.
  5. 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.
  6. 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.
  7. "Bosulif Approved for Previously Treated Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia". 5 September 2012. Archived from the original on 24 September 2015. Retrieved 1 November 2021.
  8. "Bosulif : EPAR - Product Information" (PDF). European Medicines Agency. Pfitzer Ltd. 9 April 2013. Archived (PDF) from the original on 3 January 2014. Retrieved 3 January 2014.
  9. "Bosulif 100mg and 500mg Tablets - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Pfitzer Limited. 7 June 2013. Archived from the original on 3 January 2014. Retrieved 3 January 2014.
  10. "BOSULIF (bosutinib monohydrate) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]". DailyMed. Pfitzer Inc. September 2013. Archived from the original on 3 January 2014. Retrieved 3 January 2014.
  11. 11.0 11.1 11.2 11.3 11.4 11.5 "Bosulif (bosutinib) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 3 January 2014. Retrieved 3 January 2014.
  12. 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.
  13. Bosutinib. livertox.nih.gov. 2012. Archived from the original on 3 April 2018. Retrieved 1 November 2021.

External links

External sites:
Identifiers: