|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Metabolism||Hepatic (CYP3A & CYP2D6)|
|Excretion||Feces (80%), urine (10%)|
Ibrutinib (USAN, 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 and in February 2014 for the treatment of chronic lymphocytic leukemia. It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton's tyrosine kinase (BTK). 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.
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.
Very common (>10% frequency):
- Increased serum creatinine
- Musculoskeletal pain
- Peripheral oedema
- URI infection
- Abdominal pain
- Decreased appetite
- UTI infection
- Skin infections
- Muscle spasms
- Dyspepsia (indigestion)
- Epistaxis (nosebleeds)
Common (1-10% frequency):
- Haemorrhage (grade 3/4)
- Secondary primary malignancies
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. 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 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.
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. 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. 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. It was approved by the US FDA on November 13, 2013 for the treatment of mantle cell lymphoma. On Feb. 12, 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL). Further expansion to 17p deletion in CLL was approved 28 July 2014.
- Statement on a Nonproprietary Name Adopted by the USAN Council
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- "Ohio State Cancer Research Played a Significant Role in FDA Approval of Important New CLL Drug". The Ohio State University. 14 February 2014.
- BTK inhibitor PCI-32765, National Cancer Institute Drug Dictionary
- Official Imbruvica patient website