Ibrutinib

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.

Ibrutinib
Clinical data
Trade namesImbruvica, Ibrutix
AHFS/Drugs.comMonograph
License data
Pregnancy
category
  • AU: D
  • US: D (Evidence of risk)
    Routes of
    administration
    Oral (capsules)
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Protein binding97.3%
    MetabolismHepatic (CYP3A & CYP2D6)
    Elimination half-life4–6 hours
    ExcretionFeces (80%), urine (10%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard100.232.543
    Chemical and physical data
    FormulaC25H24N6O2
    Molar mass440.4971 g·mol−1
    3D model (JSmol)

    In January 2016 ibrutinib cost US$116,600 to $155,400 a year wholesale in the United States.[1]

    Medical uses

    Ibrutinib is used to treat chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia, and as a second-line treatment for mantle cell lymphoma, marginal zone lymphoma, and chronic graft vs host disease.[2][3]

    It is a first line treatment in those with CLL who require treatment and are newly diagnosed.[4] It may also be used in CLL that relapses.[4]

    Resistance

    Both primary (inherent) and secondary (acquired) resistance has been reported in various lymphomas, including CLL and MCL.[5] 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.

    Adverse effects

    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.[2]

    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.[2]

    Pharmacology

    Ibrutinib oral bioavailability is 3.9% in a fasting state, 8.4% in a fed state, and 15.9% after consumption of grapefruit juice.[6]

    Mechanism

    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).[7][8] Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis.[9] 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.[9] This also leads to a reduction of Mcl1 levels (anti-apoptotic protein) in malignant B cells.[9] 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.[10]

    History

    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.[11]

    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.[11][12] 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.[13] Pharmacyclics was acquired by AbbVie in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.[1]

    It was approved by the US FDA on November 13, 2013 for the treatment of mantle cell lymphoma.[14] On Feb. 12, 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL).[15] It was approved for Waldenstrom's macroglobulinemia in 2015.[16]

    In March 2015 Pharmacyclics and Abbvie agreed that Abbvie would acquire Pharmacyclics for $21 billion;[17] the deal was completed that May.[18]

    In 2017 the FDA approved ibrutinib as a second line treatment for graft vs host disease. It was the first drug approved by the FDA for this condition.[19]

    Cost

    The typical cost of ibrutinib in the United States is about $148,000 a year. Preliminary 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.[20] 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.[21]

    Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme in 2018.[22]

    Brand names

    In Bangladesh it is available under the brandname Ibrutix by Beacon Pharmaceuticals.

    References

    1. Walker, Joseph (1 January 2016). "Patients Struggle With High Drug Prices: Out-of-pocket costs for pricey new drugs leave even some insured and relatively affluent patients with hard choices on how to afford them". Belleville, Illinois: Wall Street Journal. Retrieved 31 January 2019.
    2. "UK Ibrutiniib label". UK Electronic Medicines Compendium. 25 August 2016.
    3. "US Ibrutinib label" (PDF). FDA. August 2017. For updates, see FDA index page for NDA 205552
    4. "Chronic Lymphocytic Leukemia Treatment". National Cancer Institute. 1 January 1980. Retrieved 19 February 2019.
    5. Kaur V (2017). "Ibrutinib in CLL: a focus on adverse events, resistance and novel approaches beyond ibrutinib". Ann Hematol. doi:10.1007/s00277-017-2973-2. PMID 28342031.
    6. deVries R (2016). "Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults". Br J Clin Pharmacol. 81 (2): 235–45. doi:10.1111/bcp.12787. PMC 4833163. PMID 26382728.
    7. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA (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. doi:10.1182/blood-2011-10-386417. PMC 4916557. PMID 22180443.
    8. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M (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. doi:10.1182/blood-2011-11-390989. PMID 22279054.
    9. Pavlasova, G; et al. (22 September 2016). "Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis". Blood. 128 (12): 1609–13. doi:10.1182/blood-2016-04-709519. PMC 5291297. PMID 27480113.
    10. 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. doi:10.1007/s11899-012-0147-9. PMC 3584329. PMID 23296407.
    11. Shaywitz, David (April 5, 2013). "The Wild Story Behind A Promising Experimental Cancer Drug". Forbes.
    12. Langreth, Robert; Coffey, Brendan (26 February 2015). "Cancer Drug Once Bought for $7 Million May Now Fetch $18 Billion". Bloomberg.com.
    13. Sheridan, C (7 March 2012). "Companies in rapid pursuit of Btk immunokinase". Nature Biotechnology. 30 (3): 199–200. doi:10.1038/nbt0312-199. PMID 22398595.
    14. "FDA approves Imbruvica for rare blood cancer". United States Food and Drug Administration.
    15. Azvolinsky, PhD, Anna. "FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia". Cancer Network. Retrieved 14 February 2014.
    16. "News Release: FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma". FDA. January 29, 2015.
    17. Rockoff, Jonathan D.; Loftus, Peter (5 March 2015). "AbbVie to Buy Pharmacyclics in $21 Billion Deal". Wall Street Journal.
    18. Sachdev, Ameet (May 26, 2015). "AbbVie closes $21 billion deal for Pharmacyclics". Chicago Tribune.
    19. "Press Announcements - FDA approves treatment for chronic graft versus host disease". FDA. August 2, 2017.
    20. Johnson, Carolyn Y. (2018-04-18). "Science hinted that cancer patients could take less of a $148,000-a-year drug. Its maker tripled the price of a pill". The Washington Post. Retrieved 2018-04-19.
    21. Johnson, Carolyn Y. (2018-05-15). "After outcry, drugmakers decide not to triple the price of a cancer pill". The Washington Post. Retrieved 2018-06-13.
    22. "MIL-OSI Australia: $250 million investment in life changing cancer medicines – ForeignAffairs.co.nz". Foreignaffairs.co.nz. 16 July 2018. Retrieved 20 July 2018.
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