Ibrutinib

Ibrutinib
Names
Trade namesImbruvica, others
Other namesPCI-32765, CRA-032765
IUPAC name
  • 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
Clinical data
Main usesMantle cell lymphoma, chronic lymphocytic leukemia, Waldenström's macroglobulinemia, graft versus host disease[1][2]
Side effectsLow platelets, low red blood cells, low white blood cells, diarrhea, rash, bleeding, mouth inflammation[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
    Routes of
    use    		By mouth (capsules)
    Typical dose420 to 560 mg OR[1]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa614007
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only) [4][5]
    • US: ℞-only [1]
    • EU: Rx-only [2]
    • In general: ℞ (Prescription only)
    Pharmacokinetics
    Protein binding97.3%
    MetabolismLiver (CYP3A & CYP2D6)
    Elimination half-life4–6 hours
    ExcretionFeces (80%), urine (10%)
    Chemical and physical data
    FormulaC25H24N6O2
    Molar mass440.507 g·mol−1
    3D model (JSmol)
    SMILES
    • C=CC(=O)N1CCC[C@H](C1)N2C3=C(C(=N2)C4=CC=C(C=C4)OC5=CC=CC=C5)C(=NC=N3)N
    InChI
    • InChI=1S/C25H24N6O2/c1-2-21(32)30-14-6-7-18(15-30)31-25-22(24(26)27-16-28-25)23(29-31)17-10-12-20(13-11-17)33-19-8-4-3-5-9-19/h2-5,8-13,16,18H,1,6-7,14-15H2,(H2,26,27,28)/t18-/m1/s1
    • Key:XYFPWWZEPKGCCK-GOSISDBHBU

    Ibrutinib, sold under the brand name Imbruvica among others, is a medication used to treat mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenström's macroglobulinemia.[1][2] It is used in MCL and CLL when other treatments have failed.[2] Other uses may include graft versus host disease.[1] It is taken by mouth.[1]

    Common side effects include low platelets, low red blood cells, low white blood cells, diarrhea, rash, bleeding, and mouth inflammation.[1] Other side effects may include infection, heart failure, high blood pressure, other cancers, and tumor lysis syndrome.[1] Use in pregnancy may harm the baby.[1] It works by blocking Bruton's tyrosine kinase (BTK) which slows B cell division.[2]

    Ibrutinib was approved for medical use in the United States in 2013 and Europe in 2014.[6][2] It is on the World Health Organization's List of Essential Medicines as a complementary item.[7] Generic versions have been approved.[8] In the United Kingdom 4 weeks of treatment costs the NHS about £5,000 as of 2021.[9] This amount in the United States costs about 14,500 USD.[10]

    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.[5][1] BTK inhibition by ibrutinib impairs the BCR signalling pathway, which is a key dependency of malignant B cells, but it has been shown that BTK inhibition also interferes with CD40 signalling, B cell adhesion and migration.

    In the United States ibrutinib is indicated for the treatment of adults with mantle cell lymphoma (MCL) who have received at least one prior therapy, adults with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with or without 17p deletion, adults with Waldenström's macroglobulinemia (WM), adults with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy, adults with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy.[1][11][12][13][14]

    It is a first line treatment in those with CLL who require treatment and are newly diagnosed.[15] It may also be used in CLL that relapses.[15]

    Dosage

    It is usually taken at a dose of 420 to 560 mg once per day.[1]

    Side 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.[5]

    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[16] 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.[5]

    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.[17]

    Mechanism

    Ibrutinib is a potent, irreversible inhibitor of Bruton’s tyrosine kinase (BTK). It forms a covalent bond with the cysteine residue C481 in the BTK active site, leading to sustained inhibition of BTK enzymatic activity. BTK is an important signalling molecule of the B-cell antigen receptor (BCR) pathway, which is plays a role in the pathogenesis of several B-cell malignancies including mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and chronic lymphocytic leukemia (CLL). Preclinical studies have shown that ibrutinib effectively inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.[2]

    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.[18]

    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.[19] This also leads to a reduction of MCL1 levels (anti-apoptotic protein) in malignant B cells.[19] 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 (BAFF, IL-6, IL-4, and TNF-α), fibronectin engagement and stromal cell contact.

    Ibrutinib has also 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).[20][21] Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis.[19] 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.

    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.[22]

    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.[22][23] 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.[24] Pharmacyclics was acquired by AbbVie in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.[25]

    It was approved by the US Food and Drug Administration (FDA) on November 13, 2013, for the treatment of mantle cell lymphoma.[11] On February 12, 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL).[26][27] It was approved for Waldenström's macroglobulinemia in 2015.[12][28]

    In March 2015, Pharmacyclics and AbbVie agreed that Abbvie would acquire Pharmacyclics for $21 billion;[29] the deal was completed that May.[30]

    In March 2016, a new indication for ibrutinib was approved in the United States for patients with chronic lymphocytic leukemia (CLL).[31]

    In May 2016, a new indication for ibrutinib was approved in the United States for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).[32]

    In January 2017, a new indication for ibrutinib was approved in the United States for the treatment of adults with relapsed/refractory (R/R) marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy.[33]

    In August 2017, the FDA approved a new indication for ibrutinib to treat graft-versus-host disease. It was the first drug approved by the FDA for this condition.[13][14][34]

    In February 2018, a tablet formulation of ibrutinib was approved for use in the United States.[35]

    In August 2018, ibrutinib in combination with rituximab was approved in the United States for the treatment of adults with Waldenström's macroglobulinemia (WM), a rare and incurable type of non-Hodgkin's lymphoma (NHL).[36]

    In January 2019, ibrutinib in combination with obinutuzumab was approved for the treatment of adults with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).[37]

    In April 2020, the FDA expanded the indication of ibrutinib to include its combination with rituximab for the initial treatment of adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).[38] Approval was based on the E1912 trial (NCT02048813), a 2:1 randomized, multicenter, open-label, actively controlled trial of ibrutinib with rituximab compared to fludarabine, cyclophosphamide, and rituximab (FCR) in 529 adult subjects 70 years or younger with previously untreated CLL or SLL requiring systemic therapy.[38]

    Society and culture

    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.[39] 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.[40]

    Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme in 2018.[41]

    Generic ibrutinib was added to the Indian Pharmaceutical Benefits Scheme in 2020.[42]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Imbruvica- ibrutinib capsule Imbruvica- ibrutinib tablet, film coated". DailyMed. 8 April 2020. Archived from the original on 12 August 2020. Retrieved 21 April 2020.
    2. 1 2 3 4 5 6 7 "Imbruvica EPAR". European Medicines Agency (EMA). 8 July 2021. Archived from the original on 10 April 2021. Retrieved 14 July 2021.
    3. ↑ "Ibrutinib (Imbruvica) Use During Pregnancy". Drugs.com. 3 December 2019. Archived from the original on 28 March 2020. Retrieved 28 March 2020.
    4. ↑ "Imbruvica 140 mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". (emc). 16 January 2020. Archived from the original on 28 March 2020. Retrieved 28 March 2020.
    5. 1 2 3 4 "UK Ibrutinib label". UK Electronic Medicines Compendium. 25 August 2016. Archived from the original on 30 July 2019. Retrieved 3 October 2021.
    6. ↑ "Ibrutinib Monograph for Professionals". Drugs.com. Archived from the original on 10 July 2020. Retrieved 24 November 2021.
    7. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
    8. ↑ "Ibrutinib: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 24 June 2021. Retrieved 19 June 2021.
    9. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1028. ISBN 978-0857114105.
    10. ↑ "Imbruvica Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 13 September 2021. Retrieved 24 November 2021.
    11. 1 2 "FDA approves Imbruvica for rare blood cancer". U.S. Food and Drug Administration (FDA) (Press release). 13 November 2013. Archived from the original on 13 November 2013. Public Domain This article incorporates text from this source, which is in the public domain.
    12. 1 2 "FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma" (Press release). U.S. Food and Drug Administration (FDA). January 29, 2015. Archived from the original on February 1, 2015. Public Domain This article incorporates text from this source, which is in the public domain.
    13. 1 2 "FDA approves treatment for chronic graft versus host disease" (Press release). U.S. Food and Drug Administration (FDA). 2 August 2017. Archived from the original on 28 March 2020. Retrieved 28 March 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    14. 1 2 "FDA expands ibrutinib indications to chronic GVHD". U.S. Food and Drug Administration (FDA). 2 August 2017. Archived from the original on 22 April 2020. Retrieved 21 April 2020.
    15. 1 2 "Chronic Lymphocytic Leukemia Treatment". National Cancer Institute. 1 January 1980. Archived from the original on 24 April 2015. Retrieved 19 February 2019.
    16. ↑ Kaur V, Mehta P, Johnsurd J, Govindarajan R (November 2014). "Ibrutinib-associated tumor lysis syndrome in a patient with chronic lymphocytic leukemia". Blood. 124 (23): 3503–5. doi:10.1182/blood-2014-08-591875. PMID 25431479.
    17. ↑ 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.
    18. ↑ 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.
    19. 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. PMC 5291297. PMID 27480113.
    20. ↑ Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA (February 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.
    21. ↑ 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.
    22. 1 2 Shaywitz, David (April 5, 2013). "The Wild Story Behind A Promising Experimental Cancer Drug". Forbes. Archived from the original on March 28, 2021. Retrieved October 3, 2021.
    23. ↑ Langreth, Robert; Coffey, Brendan (26 February 2015). "Cancer Drug Once Bought for $7 Million May Now Fetch $18 Billion". Bloomberg.com. Archived from the original on 2019-01-27. Retrieved 2021-10-03.
    24. ↑ 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. S2CID 205266502.
    25. ↑ 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". The Wall Street Journal. Archived from the original on 29 April 2021. Retrieved 31 January 2019.
    26. ↑ "Imbruvica (ibrutinib) Capsules". U.S. Food and Drug Administration (FDA). 8 April 2015. Archived from the original on 12 July 2020. Retrieved 21 April 2020.
    27. ↑ Azvolinsky, Anna. "FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia". Cancer Network. Archived from the original on 22 February 2014. Retrieved 14 February 2014.
    28. ↑ "Imbruvica (ibrutinib) Now Approved to Treat Waldenstrom's Macroglobulinemia in Europe". AbbVie. 10 July 2015. Archived from the original on 13 July 2020. Retrieved 21 April 2020.
    29. ↑ Rockoff, Jonathan D.; Loftus, Peter (5 March 2015). "AbbVie to Buy Pharmacyclics in $21 Billion Deal". The Wall Street Journal. Archived from the original on 19 July 2021. Retrieved 3 October 2021.
    30. ↑ Sachdev, Ameet (May 26, 2015). "AbbVie closes $21 billion deal for Pharmacyclics". Chicago Tribune. Archived from the original on June 29, 2021. Retrieved October 3, 2021.
    31. ↑ "Imbruvica (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia". AbbVie (Press release). 4 March 2016. Archived from the original on 22 April 2020. Retrieved 21 April 2020.
    32. ↑ "U.S. FDA Expands Imbruvica (ibrutinib) Label to Include Overall Survival Data in Previously Untreated Chronic Lymphocytic Leukemia (CLL) and New Indication for Small Lymphocytic Lymphoma (SLL) Patients". AbbVie (Press release). 9 May 2016. Archived from the original on 22 April 2020. Retrieved 21 April 2020.
    33. ↑ "U.S. FDA Approves Imbruvica (ibrutinib) as First Treatment Specifically Indicated for Relapsed/Refractory Marginal Zone Lymphoma (MZL) - a Rare Type of Non-Hodgkin's Lymphoma". AbbVie (Press release). 19 January 2017. Archived from the original on 22 April 2020. Retrieved 21 April 2020.
    34. ↑ "U.S. FDA Approves Imbruvica (ibrutinib) as First Approved Treatment Specifically for Adults with Chronic Graft-Versus-Host-Disease (cGVHD) -- A Serious, Potentially Life-Threatening Condition -- After Failure of One or More Lines of Systemic Therapy". AbbVie (Press release). 2 August 2017. Archived from the original on 22 April 2020. Retrieved 21 April 2020.
    35. ↑ "Drug Approval Package: Imbruvica (ibrutinib)". U.S. Food and Drug Administration (FDA). 26 October 2018. Archived from the original on 20 September 2020. Retrieved 22 April 2020.
    36. ↑ "AbbVie Announces Imbruvica (ibrutinib) Plus Rituximab Approval by U.S. FDA as First Chemotherapy-Free Combination Treatment in Adults with Waldenström's Macroglobulinemia, a Rare Type of Blood Cancer". AbbVie (Press release). 27 August 2018. Archived from the original on 22 April 2020. Retrieved 21 April 2020.
    37. ↑ "AbbVie Announces U.S. FDA Approval of Imbruvica (ibrutinib) Plus Obinutuzumab (GAZYVA) - First Chemotherapy-Free, Anti-CD20 Combination Regimen Approved for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) in Previously Untreated Patients". AbbVie (Press release). 28 January 2019. Archived from the original on 22 April 2020. Retrieved 21 April 2020.
    38. 1 2 "FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia". U.S. Food and Drug Administration (FDA). 21 April 2020. Archived from the original on 22 April 2020. Retrieved 21 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    39. ↑ 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. Archived from the original on 2018-04-18. Retrieved 2018-04-19.
    40. ↑ Johnson, Carolyn Y. (2018-05-15). "After outcry, drugmakers decide not to triple the price of a cancer pill". The Washington Post. Archived from the original on 2018-06-13. Retrieved 2018-06-13.
    41. ↑ "MIL-OSI Australia: $250 million investment in life changing cancer medicines – ForeignAffairs.co.nz". Foreignaffairs.co.nz. 16 July 2018. Archived from the original on 20 July 2018. Retrieved 20 July 2018.
    42. ↑ "Cost-effectiveness Ibrutinib [Imbruvica] In India, USA, UK, And Australia – Medixocentre.com". Medixocentre.com. 10 February 2020. Archived from the original on 25 February 2020. Retrieved 15 February 2020.
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