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Ibrutinib

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Ibrutinib
200px
Systematic (IUPAC) name
1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
Clinical data
Trade names Imbruvica
Licence data US FDA:link
  • US: D (Evidence of risk)
Pharmacokinetic data
Protein binding 97.3%
Metabolism Hepatic (CYP3A & CYP2D6)
Half-life 4-6 hours
Excretion Feces (80%), urine (10%)
Identifiers
936563-96-1
L01XE27
PubChem CID 24821094
ChemSpider 26637187
ChEBI CHEBI:76612
ChEMBL CHEMBL1873475
Chemical data
Formula C25H24N6O2
440.4971

Ibrutinib (USAN,[1] also known as PCI-32765 and marketed under the name Imbruvica) is an anticancer drug targeting B-cell malignancies. It was approved by the US FDA in November 2013 for the treatment of mantle cell lymphoma[2] and in February 2014 for the treatment of chronic lymphocytic leukemia.[3] It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase (BTK).[4][5][6] Ibrutinib is currently under development by Pharmacyclics, Inc and Johnson & Johnson's Janssen Pharmaceutical division for additional B-cell malignancies including diffuse large B-cell lymphoma and multiple myeloma.[7][8]

Medical uses

It is FDA-approved as a treatment for mantle cell lymphoma[9] and chronic lymphocytic leukemia.[3]

Mantle cell lymphoma

A single arm trial of ibrutinib was performed in 111 people with mantle cell lymphoma who had previously been treated with at least one other drug. The median number of prior treatments was 3; 11% had undergone prior stem cell transplant. At baseline, 39% had at least one tumor greater than 5 cm in diameter. In these people with advanced disease, 66% had a response to therapy (ORR) including 17% with a complete response. The median duration of tumor response was 17.5 months.[10]

Adverse effects

Adverse effects by incidence:[9][11]

Very common (>10% frequency):

  • Increased serum creatinine
  • Thrombocytopaenia
  • Diarrhoea
  • Haemorrhage
  • Neutropaenia
  • Anaemia
  • Fatigue
  • Musculoskeletal pain
  • Peripheral oedema
  • URI infection
  • Nausea
  • Bruising
  • Dyspnoea
  • Constipation
  • Rash
  • Abdominal pain
  • Vomiting
  • Decreased appetite
  • Cough
  • Pyrexia
  • Stomatitis
  • UTI infection
  • Pneumonia
  • Skin infections
  • Asthenia
  • Muscle spasms
  • Dizziness
  • Sinusitis
  • Headache
  • Dehydration
  • Dyspepsia (indigestion)
  • Petechiae
  • Arthralgia
  • Epistaxis (nosebleeds)

Common (1-10% frequency):

  • Haemorrhage (grade 3/4)
  • Secondary primary malignancies

Mechanism

Ibrutinib has been reported to reduce CLL cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor.[12][13] Together, these data are consistent with a mechanistic model whereby ibrutinib blocks BCR signaling, which drives cells into apoptosis and/or disrupts cell migration and adherence to protective tumour microenvironments.

In preclinical studies on chronic lymphocytic leukemia (CLL) cells, ibrutinib has been reported to promote apoptosis, inhibit proliferation, and also prevent CLL cells from responding to survival stimuli provided by the microenvironment[14] Treatment of activated CLL cells with ibrutinib resulted in inhibition of Btk tyrosine phosphorylation and also effectively abrogated downstream survival pathways activated by this kinase including ERK1/2, PI3K, and NF-κB. Additionally, ibrutinib inhibited proliferation of CLL cells in vitro, effectively blocking survival signals provided externally to CLL cells from the microenvironment including soluble factors (CD40L, BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.

In early clinical studies, the activity of ibrutinib has been described to include a rapid reduction in lymphadenopathy accompanied by a transient lymphocytosis, suggesting that the drug might have direct effects on cell homing or migration to factors in tissue microenvironments.[15]

History

Ibrutinib was first designed and synthesized at Celera Genomics which reported in 2007 a structure-based approach for creating a series of small molecules that inactivate BTK through covalent binding to cysteine-481 near the ATP binding domain of BTK.[4] These small molecules irreversibly inhibited BTK by using a Michael acceptor for binding to the target cysteine. In April 2006, Pharmacyclics acquired Celera’s small molecule BTK inhibitor discovery program, which included a compound, PCI-32765 that was subsequently chosen for further preclinical development based on the discovery of anti-lymphoma properties in vivo.[16] Since 2006, Pharmacyclics’ scientists have advanced the molecule into clinical trials and identified specific clinical indications for the drug. It also has potential effects against autoimmune arthritis.[17] It was approved by the US FDA on November 13, 2013 for the treatment of mantle cell lymphoma.[2] On Feb. 12, 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL).[18] Further expansion to 17p deletion in CLL was approved 28 July 2014.

References

  1. Statement on a Nonproprietary Name Adopted by the USAN Council
  2. 2.0 2.1 "FDA approves Imbruvica for rare blood cancer". United States Food and Drug Administration. 
  3. 3.0 3.1 Azvolinsky, PhD, Anna. "FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia". Cancer Network. Retrieved 14 February 2014. 
  4. 4.0 4.1 Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC et al. (Jan 2007). "Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase". ChemMedChem 2 (1): 58–61. PMID 17154430. doi:10.1002/cmdc.200600221. 
  5. "Celera Genomics Announces Sale of Therapeutic Programs to Pharmacyclics". Celera: Personalizing Disease Management: Press Releases. 
  6. US patent 7514444, Honigberg L, Verner E, Pan Z, "Inhibitors of Bruton's Tyrosine Kinase", published 7 April 2009, issued 28 December 2006, assigned to Pharmacyclics Inc 
  7. "Collaborative Development and Worldwide License Agreement for Investigational Anti-Cancer Drug, PCI-32765". PRNewswire-FirstCall. Janssen Biotech, Inc. 8 December 2011. 
  8. "Clinical trials involve ibrutinib". ClinicalTrials.gov. 
  9. 9.0 9.1 "Imbruvica (Ibrutinib)". Medscape Reference. WebMD. Retrieved 13 January 2014. 
  10. "Highlights of Imbruvica Prescribing Information" (PDF). United States Food and Drug Administration. 
  11. "IMBRUVICA (ibrutinib) capsule [Pharmacyclics, Inc]". DailyMed. Pharmacyclics, Inc. November 2013. Retrieved 13 January 2013. 
  12. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG et al. (Feb 2012). "The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo". Blood 119 (5): 1182–1189. PMID 22180443. doi:10.1182/blood-2011-10-386417. 
  13. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ et al. (Mar 2012). "The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia". Blood 119 (11): 2590–2594. PMID 22279054. doi:10.1182/blood-2011-11-390989. 
  14. Seda V, Mraz M (Mar 2015). "B-cell receptor signalling and its crosstalk with other pathways in normal and malignant cells". European Journal of Haematology 94 (3): n/a. PMID 25080849. doi:10.1111/ejh.12427. 
  15. Brown JR (2013). "Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials". Curr Hematol Malig Rep 8 (1): 1–6. PMC 3584329. PMID 23296407. doi:10.1007/s11899-012-0147-9. 
  16. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B et al. (Jul 2010). "The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy". Proceedings of the National Academy of Sciences of the United States of America 107 (29): 13075–80. PMC 2919935. PMID 20615965. doi:10.1073/pnas.1004594107. 
  17. Chang BY, Huang MM, Francesco M, Chen J, Sokolove J, Magadala P et al. (2011). "The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells". Arthritis Research & Therapy 13 (4): R115. PMC 3239353. PMID 21752263. doi:10.1186/ar3400. 
  18. "Ohio State Cancer Research Played a Significant Role in FDA Approval of Important New CLL Drug". The Ohio State University. 14 February 2014. 

External links