Ibrutinib Explained

Width:200
Tradename:Imbruvica, others
Dailymedid:Ibrutinib
Pregnancy Au:D
Pregnancy Au Comment:[1]
Routes Of Administration:By mouth
Atc Prefix:L01
Atc Suffix:EL01
Legal Au:S4
Legal Au Comment:[2]
Legal Ca:Rx-only
Legal Ca Comment:[3]
Legal Uk:POM
Legal Uk Comment:[4]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Status:Rx-only
Protein Bound:97.3%
Metabolism:Hepatic (CYP3A & CYP2D6)
Elimination Half-Life:4–6 hours
Excretion:Feces (80%), urine (10%)
Cas Number:936563-96-1
Pubchem:24821094
Iuphar Ligand:6912
Drugbank:DB09053
Chemspiderid:26637187
Unii:1X70OSD4VX
Kegg:D10223
Chebi:76612
Chembl:1873475
Pdb Ligand:1E8
Synonyms:PCI-32765, CRA-032765
Iupac Name:1-[(3''R'')-3-[4-Amino-3-(4-phenoxyphenyl)-1''H''-pyrazolo[3,4-''d'']pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
C:25
H:24
N:6
O:2
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
Stdinchi: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
Stdinchikey:XYFPWWZEPKGCCK-GOSISDBHBU

Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia.[5] Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.[6]

It is on the World Health Organization's List of Essential Medicines.[7]

Medical uses

Ibrutinib is indicated for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic graft versus host disease (cGVHD).[8] [9]

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.

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,[10] 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.[11]

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.[12]

Mechanism

Ibrutinib is a potent, irreversible inhibitor of Bruton's tyrosine kinase (BTK). The acrylamide group of ibrutinib 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 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.[5]

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.[13]

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 (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).[14] [15] Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis.[16] 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.[17]

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.[17] [18] 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.[19] Pharmacyclics was acquired by AbbVie in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.[20]

It was approved by the US Food and Drug Administration (FDA) in November 2013, for the treatment of mantle cell lymphoma.[21] In February 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL).[22] [23] It was approved for Waldenström's macroglobulinemia in 2015.[24] [25]

In March 2015, Pharmacyclics and AbbVie agreed that Abbvie would acquire Pharmacyclics for $21 billion;[26] the deal was completed that May.[27]

In March 2016, a new indication for ibrutinib was approved in the United States for patients with chronic lymphocytic leukemia (CLL).[28]

In May 2016, a new indication for ibrutinib was approved in the United States for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).[29]

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.[30]

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.[31] [32] [33]

In February 2018, a tablet formulation of ibrutinib was approved for use in the United States.[34]

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).[35]

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).[36]

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).[37] 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.

Society and culture

Economics

Janssen Pharmaceutica and Pharmacyclics introduced a new single dose tablet formulation with a flat pricing structure in the first half of 2018 and discontinued the capsule formulation. This caused an outcry as it was perceived to triple the cost of the drug to the average patient.[38]

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.[39]

Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme in 2018.[40]

Generic ibrutinib was added to the Indian Pharmaceutical Benefits Scheme in 2020.[41]

Imbruvica was named in 2023 as one of the first 10 drugs to be subjected to Medicare price negotiations under the Inflation Reduction Act.[42]

Further reading

External links

Notes and References

  1. Web site: Ibrutinib (Imbruvica) Use During Pregnancy . Drugs.com . 3 December 2019 . 28 March 2020.
  2. Web site: Prescription medicines: registration of new chemical entities in Australia, 2015 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 10 April 2023.
  3. Web site: Regulatory Decision Summary for Imbruvica . Drug and Health Products Portal . 4 August 2023 . 2 April 2024.
  4. Web site: Imbruvica 140 mg Film-Coated Tablets - Summary of Product Characteristics (SmPC) . (emc) . 16 January 2020 . 28 March 2020.
  5. Web site: Imbruvica EPAR . European Medicines Agency (EMA) . 8 July 2021 . 14 July 2021.
  6. Xiao L, Salem JE, Clauss S, Hanley A, Bapat A, Hulsmans M, Iwamoto Y, Wojtkiewicz G, Cetinbas M, Schloss MJ, Tedeschi J, Lebrun-Vignes B, Lundby A, Sadreyev RI, Moslehi J, Nahrendorf M, Ellinor PT, Milan DJ . 6 . Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase . Circulation . 142 . 25 . 2443–2455 . December 2020 . 33092403 . 9661397 . 10.1161/CIRCULATIONAHA.120.049210 .
  7. Book: ((World Health Organization)) . World Health Organization model list of essential medicines: 22nd list (2021) . 2021 . 10665/345533 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2021.02 . free .
  8. Web site: Imbruvica- ibrutinib capsule Imbruvica- ibrutinib tablet, film coated . DailyMed . 8 April 2020 . 21 April 2020.
  9. Web site: FDA approves ibrutinib for pediatric patients with chronic graft versus host disease, including a new oral suspension . U.S. Food and Drug Administration (FDA) . 24 August 2022 . 24 August 2022.
  10. Kaur V, Mehta P, Johnsurd J, Govindarajan R . Ibrutinib-associated tumor lysis syndrome in a patient with chronic lymphocytic leukemia . Blood . 124 . 23 . 3503–3505 . November 2014 . 25431479 . 10.1182/blood-2014-08-591875 . free .
  11. Web site: UK Ibrutinib label. UK Electronic Medicines Compendium. 25 August 2016. 20 November 2016. 30 July 2019. https://web.archive.org/web/20190730044702/https://www.medicines.org.uk/emc/medicine/29383. dead.
  12. de Vries R, Smit JW, Hellemans P, Jiao J, Murphy J, Skee D, Snoeys J, Sukbuntherng J, Vliegen M, de Zwart L, Mannaert E, de Jong J . 6 . Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults . British Journal of Clinical Pharmacology . 81 . 2 . 235–245 . February 2016 . 26382728 . 4833163 . 10.1111/bcp.12787 .
  13. Brown JR . Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials . Current Hematologic Malignancy Reports . 8 . 1 . 1–6 . March 2013 . 23296407 . 3584329 . 10.1007/s11899-012-0147-9 .
  14. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA . 6 . 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 . February 2012 . 22180443 . 4916557 . 10.1182/blood-2011-10-386417 .
  15. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M . 6 . 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 . March 2012 . 22279054 . 10.1182/blood-2011-11-390989 . free .
  16. Pavlasova G, Borsky M, Seda V, Cerna K, Osickova J, Doubek M, Mayer J, Calogero R, Trbusek M, Pospisilova S, Davids MS, Kipps TJ, Brown JR, Mraz M . 6 . Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis . Blood . 128 . 12 . 1609–1613 . September 2016 . 27480113 . 5291297 . 10.1182/blood-2016-04-709519 .
  17. News: Shaywitz D . The Wild Story Behind A Promising Experimental Cancer Drug. Forbes. 5 April 2013.
  18. News: Langreth R, Coffey B . Cancer Drug Once Bought for $7 Million May Now Fetch $18 Billion. Bloomberg.com. 26 February 2015.
  19. Sheridan C . Companies in rapid pursuit of Btk immunokinase . Nature Biotechnology . 30 . 3 . 199–200 . March 2012 . 22398595 . 10.1038/nbt0312-199 . 205266502 .
  20. Web site: 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 . . 1 January 2016 . 31 January 2019 . Walker J . subscription .
  21. FDA approves Imbruvica for rare blood cancer . https://web.archive.org/web/20131113202312/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm . dead . 13 November 2013 . U.S. Food and Drug Administration (FDA) . 13 November 2013.
  22. Web site: Imbruvica (ibrutinib) Capsules . U.S. Food and Drug Administration (FDA) . 8 April 2015 . 21 April 2020.
  23. Web site: Azvolinsky A . FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia. Cancer Network. 14 February 2014. 22 February 2014. https://web.archive.org/web/20140222170346/http://www.cancernetwork.com/news/fda-approves-ibrutinib-chronic-lymphocytic-leukemia. dead.
  24. FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma . https://web.archive.org/web/20150201035442/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm . dead . 1 February 2015 . U.S. Food and Drug Administration (FDA) . 29 January 2015.
  25. Web site: Imbruvica (ibrutinib) Now Approved to Treat Waldenstrom's Macroglobulinemia in Europe . AbbVie . 10 July 2015 . 21 April 2020 . 13 July 2020 . https://web.archive.org/web/20200713042931/https://news.abbvie.com/news/imbruvica-ibrutinib-now-approved-to-treat-waldenstroms-macroglobulinemia-in-europe.htm . dead .
  26. News: Rockoff JD, Loftus P . AbbVie to Buy Pharmacyclics in $21 Billion Deal. The Wall Street Journal. 5 March 2015 . subscription .
  27. News: Sachdev A . AbbVie closes $21 billion deal for Pharmacyclics. Chicago Tribune. 26 May 2015.
  28. Imbruvica (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia . AbbVie . 4 March 2016 . 21 April 2020 . 22 April 2020 . https://web.archive.org/web/20200422052916/https://news.abbvie.com/news/imbruvica-ibrutinib-approved-by-us-fda-for-first-line-treatment-chronic-lymphocytic-leukemia.htm . dead .
  29. 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 . 9 May 2016 . 21 April 2020 . 22 April 2020 . https://web.archive.org/web/20200422052902/https://news.abbvie.com/news/us-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.htm . dead .
  30. 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 . 19 January 2017 . 21 April 2020.
  31. FDA approves treatment for chronic graft versus host disease. U.S. Food and Drug Administration (FDA) . 2 August 2017 . 28 March 2020 .
  32. Web site: FDA expands ibrutinib indications to chronic GVHD . U.S. Food and Drug Administration (FDA) . 2 August 2017 . 21 April 2020.
  33. 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 . 2 August 2017 . 21 April 2020.
  34. Web site: Drug Approval Package: Imbruvica (ibrutinib) . U.S. Food and Drug Administration (FDA) . 26 October 2018 . 22 April 2020.
  35. 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 . 27 August 2018 . 21 April 2020.
  36. 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 . 28 January 2019 . 21 April 2020.
  37. Web site: FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia . U.S. Food and Drug Administration (FDA). 21 April 2020 . 21 April 2020.
  38. News: Johnson CY . Science hinted that cancer patients could take less of a $148,000-a-year drug. Its maker tripled the price of a pill. . . 18 April 2018 . 19 April 2018 .
  39. News: Johnson CY . After outcry, drugmakers decide not to triple the price of a cancer pill.. . 15 May 2018 . 13 June 2018 .
  40. Web site: MIL-OSI Australia: $250 million investment in life changing cancer medicines – ForeignAffairs.co.nz . Foreignaffairs.co.nz . 20 July 2018 . 16 July 2018 . 20 July 2018 . https://web.archive.org/web/20180720080941/https://foreignaffairs.co.nz/2018/07/16/mil-osi-australia-250-million-investment-in-life-changing-cancer-medicines/ . dead .
  41. Web site: Cost-effectiveness Ibrutinib [Imbruvica] In India, USA, UK, And Australia – Medixocentre.com ]. Medixocentre.com . 15 February 2020 . 10 February 2020.
  42. Web site: 2023-08-29 . CMS Releases List of 10 Drugs Subject to Price Negotiation Under IRA . 2024-03-17 . AJMC . en.

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