Bosutinib

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Bosutinib
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Systematic (IUPAC) name
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile
Clinical data
Trade names Bosulif
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • US: D (Evidence of risk)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Protein binding 94–96%
Metabolism By CYP3A4, to inactive metabolites
Biological half-life 22.5±1.7 hours
Excretion Foecal (91.3%) and renal (3%)
Identifiers
CAS Number 380843-75-4 N
ATC code L01XE14 (WHO)
PubChem CID: 5328940
IUPHAR/BPS 5710
ChemSpider 4486102 YesY
UNII 5018V4AEZ0 YesY
ChEBI CHEBI:39112 YesY
ChEMBL CHEMBL288441 YesY
Chemical data
Formula C26H29Cl2N5O3
Molecular mass 530.446 g/mol
  • 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) YesY
  • Key:UBPYILGKFZZVDX-UHFFFAOYSA-N YesY
 NYesY (what is this?)  (verify)

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.[1][2] Originally synthesized by Wyeth, it is being developed by Pfizer.

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.[3][4][5][6]

Adverse effects

Adverse effects by incidence:[7]
Very common (>10% frequency):

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  • Diarrhoea (~82%)
  • 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):

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  • 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):

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Contraindications

Bosutinib only has two known absolute contraindications, which are: known hypersensitivity to bosutinib and liver impairment.[7][8]

Interactions

Bosutinib is both a substrate and an inhibitor of P-glycoprotein (P-gp) and CYP3A4.[9] Hence P-gp and CYP3A4 inhibitors may increase plasma levels of bosutinib.[9] Likewise CYP3A4 inducers may reduce plasma concentrations of bosutinib.[9] 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.[9]

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.[8] Mutagenic and clastogenic effects were not detected in vitro.[8]

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).[9][10] 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.[9]

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

See also

References

  1. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ 7.0 7.1 Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ 8.0 8.1 8.2 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Derek Lowe, In The Pipeline (blog), "Bosutinib: Don't Believe the Label!"

External links

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