Ibrutinib

Ibrutinib
Clinical data
Trade names Imbruvica
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 binding 97.3%
    Metabolism Hepatic (CYP3A & CYP2D6)
    Elimination half-life 4–6 hours
    Excretion Feces (80%), urine (10%)
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard 100.232.543 Edit this at Wikidata
    Chemical and physical data
    Formula C25H24N6O2
    Molar mass 440.4971
    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.[1]

    According to the Wall Street Journal in January 2016 ibrutinib, a specialty drug, cost US$116,600 to $155,400 a year wholesale in the United States.

    Medical uses

    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.[2][3]

    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]

    Clinical 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.[4]

    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).[5][6] Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis.[7] 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.[7][8] This also leads to a reduction of Mcl1 levels (anti-apoptotic protein) in malignant B cells.[7] 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.[9]

    Resistance

    Both primary (inherent) and secondary (acquired) resistance has been reported in various lymphomas, including CLL and MCL.[10] 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.

    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]

    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 August 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]

    Pricing strategy

    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.[20]

    Janssen Pharmaceutica and Pharmacyclics have since reversed course on the proposed pricing increase. [21]

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

    See also

    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 1 January 2016.
    2. 1 2 3 "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. ↑ 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.
    5. ↑ 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.
    6. ↑ 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.
    7. 1 2 3 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. PMID 27480113.
    8. ↑ 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): 193–205. doi:10.1111/ejh.12427. PMID 25080849.
    9. ↑ 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.
    10. ↑ 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.
    11. 1 2 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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