|Metabolism||Hepatic (CYP3A & CYP2D6)|
|Elimination half-life||4–6 hours|
|Excretion||Feces (80%), urine (10%)|
|Chemical and physical data|
|Molar mass||440.4971 g·mol−1|
|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. It is used to treat B cell cancers like mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia.
In January 2016 ibrutinib cost US$116,600 to $155,400 a year wholesale in the United States.
Ibrutinib is used to treat chronic lymphocytic leukemia (CLL), Waldenstrom's macroglobulinemia, and as a second-line treatment for mantle cell lymphoma, marginal zone lymphoma, and chronic graft vs host disease.
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.
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.
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. Pharmacyclics was acquired by AbbVie in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.
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 in the United States is about $148,000 a year. Prelimary PK/PD focused research found that people could potentially be put on lower and less expensive regimen of ibrutinib without losing efficiency however no data showing efficiency of lower doses has been published.
Janssen Pharmaceutica and Pharmacyclics introduced a new single dose tablet formulation with a flat pricing structure in the first half of 2018 and discontinue the capsule formulation. This caused an outcry as it was perceived to triple in the cost of the drug to the average patient. Patients receiving the FDA approved and recommended doses would have seen either no price change or a price decrease with the tablet pricing structure.
Janssen Pharmaceutica and Pharmacyclics have since reversed the decision to discontinue the capsule formulation with the drug currently available in both capsule and tablet forms.
Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme in 2018.
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