|Metabolism||Hepatic (CYP3A & CYP2D6)|
|Elimination half-life||4–6 hours|
|Excretion||Feces (80%), urine (10%)|
|Chemical and physical data|
|3D model (JSmol)|
Ibrutinib (Imbruvica) is a small molecule drug that binds permanently to a protein, Bruton's tyrosine kinase (BTK), that is important in B cells; the drug is used to treat B cell cancers like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia.
Ibrutinib was created by scientists at Celera Genomics as a tool compound for studying BTK function, then developed by Pharmacyclics up to Phase II, then partnered with Johnson & Johnson. Pharmacyclics was acquired by AbbVie in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.
Ibrutinib is used to treat chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, and as a second-line treatment for mantle cell lymphoma, marginal zone lymphoma, and chronic graft vs host disease.
Very common (>10% frequency) adverse effects include pneumonia, upper respiratory tract infection, sinusitis, skin infection, low neutrophil count, low platelet counts, headache, bleeding, bruising, diarrhea, vomiting, inflammation of mouth and lips, nausea, constipation, rash, joint pain, muscle spasms, musculoskeletal pain, fever, and edema.
Common (1–10% frequency) adverse effects include sepsis, urinary tract infection, non-melanoma skin cancer (basal-cell carcinoma, squamous cell carcinoma), low leukocyte count, low lymphocyte count, interstitial lung disease, tumor lysis syndrome, high uric acid levels, dizziness, blurred vision, atrial fibrillation, subdural hematoma, nosebleeds, small bruises from broken blood vessels, high blood pressure, hives, and skin redness or blushing.
Ibrutinib oral bioavailability is 3.9% in a fasting state, 8.4% in a fed state, and 15.9% after consumption of grapefruit juice.
Ibrutinib has been reported to reduce chronic lymphocytic leukemia cell chemotaxis towards the chemokines CXCL12 and CXCL13, and inhibit cellular adhesion following stimulation at the B cell receptor (BCR). Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis. 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. This also leads to a reduction of Mcl1 levels (anti-apoptotic protein) in malignant B cells. 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.
Both primary (inherent) and secondary (acquired) resistance has been reported in various lymphomas, including CLL and MCL. Resistance may arise due to mutations that impair the affinity of ibrutinib for BTK, or due to alterations in pathways downstream of BTK and may confer BCR signaling independence in resistant clones.
Ibrutinib was created by scientists at Celera Genomics as a tool compound for studying BTK function; it covalently binds its target which is ideal for a reagent but generally not considered ideal for drugs.
In 2006, in the course of acquiring an HDAC-focused program from Celera after its own initial discovery program had failed, Pharmacyclics also picked up Celera's small molecule BTK inhibitor discovery program for $2M in cash and $1M in stock and named the tool compound PCI-32765. In 2011 after the drug had completed Phase II trials, Johnson & Johnson and Pharmacyclics agreed to co-develop the drug, and J&J paid Pharmacyclics $150 million upfront and $825 million in milestones.
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). It was approved for Waldenstrom's macroglobulinemia in 2015.
The typical cost of Ibrutinib (Imbruvica) in the United States is about $148,000 a year, but recent research found that patients could be put on lower and less expensive regimen of Ibrutinib without losing efficiency. In response to this, Janssen Pharmaceutica and Pharmacyclics changed their pricing strategy to a fixed price of approximately $400 per pill regardless of the dosage. This caused an increase of around triple in the cost of the drug to the average patient.
Janssen Pharmaceutica and Pharmacyclics have since reversed course on the proposed pricing increase. 
Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme in 2018.
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