Description
Ibrutinib (CAS: 936563-96-1) is a first-in-class,potent, orally administered covalently-binding inhibitor of BTK. In November 2013, the US FDA approved ibrutinib (also referred to as PCI-32765), for the treatment of patients with mantle cell lymphoma (MCL) who had received at least one prior therapy. Ibrutinib is a potent inhibitor of BTK that binds covalently to Cys-481 in the active site of BTK, resulting in inhibition of kinase activity. Ibrutinib does have significant activity against 19 other kinases, including seven with a cognate cysteine residue. These include BLK, BMX, ITK, TEC, EGFR, ERBB2, and JAK3.
Originator
Celera/Pharmacyclics (United States)
Uses
Ibrutinib is a highly selective Bruton’s tyrosine kinase (Btk) irreversible inhibitor.
Definition
ChEBI: Ibrutinib is a member of the class of acrylamides that is (3R)-3-[4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]piperidine in which the piperidine nitrogen is replaced by an acryloyl group. A selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase, it is used for treatment of B-cell malignancies. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is a pyrazolopyrimidine, an aromatic amine, an aromatic ether, a member of acrylamides, a N-acylpiperidine and a tertiary carboxamide.
Indications
Ibrutinib is a non-receptor Bruton's tyrosine kinase inhibitor approved for the treatment of relapsed chronic lymphocytic leukemia(CLL), mantle cell lymphoma (MCL) and WaldenstrÖm's Macroglobulinemia (WM).
General Description
Class: non-receptor tyrosine kinase
Treatment: CLL, MCL
Oral bioavailability = 4% (fasted), 8% (fed)
Elimination half-life = 3.2 h
Protein binding = 97.3%
Side effects
The more common side effects of Ibrutinib are diarrhoea and bleeding. Therefore, you should drink plenty of water during treatment, in order to reduce the risk of dehydration using diarrhoea. Bleeding problems can be serious and may even lead to death. This may be manifested by blood or black stools (that look like tar); pink or brown urine; accidental bleeding, or severe or uncontrollable bleeding; spitting up blood or vomit that looks like coffee grounds; coughing up blood; bruising or small red or purple spots on the skin; dizziness; confusing changes in speech; or a headache that lasts for a long time or is severe. Prompt medical attention is needed if a serious condition develops.
Other possible side effects are: increased risk of infection, fever, chills, weakness, confusion, or other signs or symptoms of infection; increased risk of heart disease, rapid and irregular heartbeat; dizziness; lightheadedness; shortness of breath; swelling of the feet, ankles, or legs; discomfort in the chest; or feeling lightheaded. High blood pressure, reduced blood counts, second primary cancer and tumour lysis syndrome (TLS). Different disease treatments exhibit different adverse effects, so the above side effects may not occur in full.
Synthesis
Condensation of commercially available 4-phenoxybenzoyl
chloride (88) with malononitrile followed by acidic quench and
O-methylation with dimethyl sulfate furnished vinyl dinitrile 89
in 84% yield over the three-step sequence. Next, treatment with
hydrazine hydrate in refluxing ethanol secured aminopyrazole 90
and this was followed by treatment with neat formamide at elevated
temperature to furnish pyrimidopyrazole 91 in excellent
conversion. Selective alkylation of the pyrazole nitrogen with commercially-
available (S)-piperidinyl tosylate (92) proceeded in 32%
yield. Finally, liberation of the amide followed by pH adjustment
and amide bond formation with acrolyl chloride furnished ibrutinib
(XI) in 50% over the three-step sequence.
Drug interactions
Potentially hazardous interactions with other drugs
Anti-arrhythmics: concentration possibly increased
by amiodarone and dronedarone - avoid or reduce
dose of ibrutinib.
Antibacterials: concentration possibly increased
by ciprofloxacin, clarithromycin, erythromycin and
telithromycin - avoid or reduce dose of ibrutinib;
concentration reduced by rifampicin - avoid.
Antidepressants: concentration possibly reduced by
St John’s wort - avoid.
Antiepileptics: concentration possibly reduced by
carbamazepine, fosphenytoin, phenobarbital and
phenytoin - avoid.
Antifungals: concentration possibly increased
by fluconazole, itraconazole, ketoconazole and
voriconazole - avoid or reduce dose of ibrutinib
.
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Antivirals: concentration possibly increased by
atazanavir, darunavir, fosamprenavir, indinavir,
ritonavir and saquinavir - avoid or reduce dose of
ibrutinib.
Aprepitant: concentration possibly increased - avoid
or reduce dose of ibrutinib.
Calcium channel blockers: concentration possibly
increased by diltiazem or verapamil - avoid or reduce
dose of ibrutinib.
Cobicistat: concentration possibly increased, avoid or
reduce dose of ibrutinib.
Cytotoxics: concentration possibly increased by
crizotinib - avoid or reduce dose of ibrutinib;
concentration possibly increased by imatinib -
reduce dose of ibrutinib.
Grapefruit juice and Seville oranges: avoid.
Metabolism
Ibrutinib is metabolised primarily by CYP3A4 to
produce a dihydrodiol metabolite with an inhibitory
activity towards BTK approximately 15 times lower
than that of ibrutinib. Involvement of CYP2D6 in the
metabolism of ibrutinib appears to be minimal.
After a single oral administration of radiolabeled
[14C]-ibrutinib in healthy subjects, approximately 90%
of radioactivity was excreted within 168 hours, with the
majority (80%) excreted in the faeces and <10% in the
urine. Unchanged ibrutinib accounted for approximately
1% of the radiolabeled excretion product in faeces and
none in urine.
storage
4°C, protect from light
Mode of action
Ibrutinib(936563-96-1) is the second oral agent approved for the treatment of MCL. It works by irreversibly inhibiting Bruton’s tyrosine kinase (Btk) leading to the inhibition of B-cell receptor signaling and resulting in the reduction of malignant B-cell proliferation and induction of cell death. Btk plays an important role in the differentiation, development, proliferation, and survival of B cells via activation of cell-cycle regulators and regulating the expression of pro- and antiapoptotic proteins. Aberrant Btk activity results in a variety of B-cell malignancies including MCL. Ibrutinib inhibits Btk by irreversibly binding to cysteine-481 in the active site thereby inhibiting phosphorylation of tyrosine-223 and affecting downstream B-cell signaling pathways.
References
1) Honigberg?et al.?(2010),?The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy;?Proc. Natl. Acad. Sci. USA?107?13075 DOI:
10.1073/pnas.10045941072) Ponader?et al.?(2012),?The Bruton tyrosine kinase Inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo;?Blood?119?1182
DOI:
10.1182/blood-2011-10-3864173) De Rooij?et al.?(2012),?The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia;?Blood?119?2590
DOI:
10.1182/blood-2011-11-3909894) Pavlasoca?et al.?(2016),?Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis;?Blood?128?1609 DOI:
10.1182/blood-2016-04-7095195) Sagiv-Barfi?et al.?(2015),?Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK; Proc. Natl. Acad. Sci. USA?112?E966 DOI:
10.1073/pnas.15007121126) Weber?et al.?(2017),?Bruton's Tyrosine Kinase: An Emerging Key Player in Innate Immunity,?Front. Immunol.?8?1454 DOI:
10.3389/fimmu.2017.01454
