Bosutinib

Bosutinib
Names
Trade namesBosulif
IUPAC name
  • 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]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
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)
SMILES
  • Clc1c(OC)cc(c(Cl)c1)Nc4c(C#N)cnc3cc(OCCCN2CCN(CC2)C)c(OC)cc34
InChI
  • 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 2 3 "Bosulif". Archived from the original on 14 November 2021. Retrieved 11 January 2022.
  2. 1 2 3 4 5 6 7 8 9 10 "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. 1 2 3 4 5 6 "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.
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