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{{short description|Medication used in cancer treatment}}
{{Short description|Medication used in cancer treatment}}
{{Use dmy dates|date=August 2022}}
{{Infobox drug
{{Infobox drug
| image = Ibrutinib.svg
| image = Ibrutinib.svg
| width = 200px
| width = 200
| alt =
| alt =


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| Drugs.com = {{drugs.com|monograph|ibrutinib}}
| Drugs.com = {{drugs.com|monograph|ibrutinib}}
| MedlinePlus = a614007
| MedlinePlus = a614007
| licence_EU = yes
| licence_US = Ibrutinib
| DailyMedID = Ibrutinib
| DailyMedID = Ibrutinib
| pregnancy_AU = D
| pregnancy_AU = D
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Ibrutinib (Imbruvica) Use During Pregnancy | website=Drugs.com | date=3 December 2019 | url=https://www.drugs.com/pregnancy/ibrutinib.html | access-date=28 March 2020}}</ref>
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Ibrutinib (Imbruvica) Use During Pregnancy | website=Drugs.com | date=3 December 2019 | url=https://www.drugs.com/pregnancy/ibrutinib.html | access-date=28 March 2020}}</ref>
| pregnancy_category=
| pregnancy_category=
⚫
| routes_of_administration = [[Oral administration|By mouth]]
| dependency_liability =
| addiction_liability =
⚫
| routes_of_administration = [[Oral administration|By mouth]] ([[Capsule (pharmacy)|capsules]])
| ATCvet =
| ATC_prefix = L01
| ATC_prefix = L01
| ATC_suffix = EL01
| ATC_suffix = EL01
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<!-- Legal status -->
<!-- Legal status -->
| legal_AU = S4
| legal_AU = S4
| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2015 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015 | access-date=10 April 2023}}</ref>
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
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| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{cite web | title=Regulatory Decision Summary for Imbruvica | website=Drug and Health Products Portal | date=4 August 2023 | url=https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1706712320386 | access-date=2 April 2024}}</ref>
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_DE_comment =
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| legal_US_comment = <ref name="Imbruvica FDA label" />
| legal_US_comment = <ref name="Imbruvica FDA label" />
| legal_EU = Rx-only
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Imbruvica EPAR"/>
| legal_EU_comment = <ref name="Imbruvica EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
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}}
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'''Ibrutinib''', sold under the brand name '''Imbruvica''' among others, is a small molecule drug that inhibits B-cell proliferation and survival by [[targeted covalent inhibitor|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#B cell-related pathology|B cell cancers]]. Ibrutinib is therefore used to treat such cancers, including [[mantle cell lymphoma]], [[chronic lymphocytic leukemia]], and [[Waldenström's macroglobulinemia]].<ref name="Imbruvica FDA label" /><ref name="Imbruvica EPAR">{{cite web | title=Imbruvica EPAR | website=[[European Medicines Agency]] (EMA) | date=8 July 2021 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica | access-date=14 July 2021}}</ref> Recent computational studies reported that Ibrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis.<ref>{{Cite journal|last=Kaliamurthi|first=Satyavani|last2=Selvaraj|first2=Gurudeeban|last3=Selvaraj|first3=Chandrabose|last4=Singh|first4=Sanjeev Kumar|last5=Wei|first5=Dong-Qing|last6=Peslherbe|first6=Gilles H.|date=2021-01|title=Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19|url=https://www.mdpi.com/1422-0067/22/13/7071|journal=International Journal of Molecular Sciences|language=en|volume=22|issue=13|pages=7071|doi=10.3390/ijms22137071|pmc=PMC8267665|pmid=34209188}}</ref>
'''Ibrutinib''', sold under the brand name '''Imbruvica''' among others, is a [[small molecule]] drug that inhibits B-cell proliferation and survival by [[targeted covalent inhibitor|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#B cell-related pathology|B cell cancers]]. Ibrutinib is therefore used to treat such cancers, including [[mantle cell lymphoma]], [[chronic lymphocytic leukemia]], and [[Waldenström's macroglobulinemia]].<ref name="Imbruvica FDA label" /><ref name="Imbruvica EPAR">{{cite web | title=Imbruvica EPAR | website=[[European Medicines Agency]] (EMA) | date=8 July 2021 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/imbruvica | access-date=14 July 2021}}</ref> 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.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase | journal = Circulation | volume = 142 | issue = 25 | pages = 2443–2455 | date = December 2020 | pmid = 33092403 | pmc = 9661397 | doi = 10.1161/CIRCULATIONAHA.120.049210 }}</ref>


It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>
It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref>


==Medical uses==
==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]].<ref name=UKlabel2016/><ref name="Imbruvica FDA label">{{cite web | title=Imbruvica- ibrutinib capsule Imbruvica- ibrutinib tablet, film coated | website=DailyMed | date=8 April 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dfd0279-ff17-4ea9-89be-9803c71bab44 | access-date=21 April 2020}}</ref> 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.
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).<ref name=UKlabel2016/><ref name="Imbruvica FDA label">{{cite web | title=Imbruvica- ibrutinib capsule Imbruvica- ibrutinib tablet, film coated | website=DailyMed | date=8 April 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0dfd0279-ff17-4ea9-89be-9803c71bab44 | access-date=21 April 2020}}</ref><ref name="Imbruvica EPAR" /><ref name="FDA PR 20131113" /><ref name="FDA PR 20150129" /><ref name="FDA PR 20170802" /><ref name="FDA ibrutinib 20170802" /><ref>{{cite web | title=FDA approves ibrutinib for pediatric patients with chronic graft versus host disease, including a new oral suspension | publisher=U.S. [[Food and Drug Administration]] (FDA) | date=24 August 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ibrutinib-pediatric-patients-chronic-graft-versus-host-disease-including-new-oral | access-date=24 August 2022}}</ref>

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.<ref name="Imbruvica FDA label" /><ref name="FDA PR 20131113" /><ref name="FDA PR 20150129" /><ref name="FDA PR 20170802" /><ref name="FDA ibrutinib 20170802" />

It is a first line treatment in those with CLL who require treatment and are newly diagnosed.<ref name=NCI2019Feb/> It may also be used in CLL that relapses.<ref name=NCI2019Feb>{{cite web |title=Chronic Lymphocytic Leukemia Treatment |url=https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq |website=National Cancer Institute |access-date=19 February 2019 |language=en |date=1 January 1980}}</ref>


==Adverse effects==
==Adverse effects==
Very common (>10% frequency) adverse effects include [[pneumonia]], [[upper respiratory tract infection]], [[sinusitis]], skin infection, [[Neutropenia|low neutrophil count]], [[Thrombocytopenia|low platelet counts]], headache, bleeding, bruising, diarrhea, vomiting, [[Stomatitis|inflammation of mouth and lips]], nausea, constipation, rash, [[Arthralgia|joint pain]], muscle spasms, musculoskeletal pain, fever, and [[edema]].<ref name=UKlabel2016/>
Very common (>10% frequency) adverse effects include [[pneumonia]], [[upper respiratory tract infection]], [[sinusitis]], skin infection, [[Neutropenia|low neutrophil count]], [[Thrombocytopenia|low platelet counts]], headache, bleeding, bruising, diarrhea, vomiting, [[Stomatitis|inflammation of mouth and lips]], nausea, constipation, rash, [[Arthralgia|joint pain]], muscle spasms, musculoskeletal pain, fever, and [[edema]].<ref name=UKlabel2016/>


Common (1–10% frequency) adverse effects include [[sepsis]], [[urinary tract infection]], non-melanoma skin cancer ([[basal-cell carcinoma]], [[squamous cell carcinoma]]), [[Leukopenia|low leukocyte count]], [[Lymphocytopenia|low lymphocyte count]], [[interstitial lung disease]], [[tumor lysis syndrome]]<ref>{{cite journal |vauthors=Kaur V, Mehta P, Johnsurd J, Govindarajan R |title=Ibrutinib-associated tumor lysis syndrome in a patient with chronic lymphocytic leukemia|journal=Blood |volume=124 |issue=23 |pages=3503–5 |pmid=25431479 |doi=10.1182/blood-2014-08-591875 |date=November 2014 |doi-access=free }}</ref> [[Hyperuricemia|high uric acid levels]], [[dizziness]], blurred vision, [[atrial fibrillation]], [[subdural hematoma]], nosebleeds, [[Petechia|small bruises from broken blood vessels]], [[Hypertension|high blood pressure]], [[hives]], and skin redness or blushing.<ref name=UKlabel2016>{{cite web|title=UK Ibrutinib label|url=https://www.medicines.org.uk/emc/medicine/29383|publisher=UK Electronic Medicines Compendium|date=25 August 2016}}</ref>
Common (1–10% frequency) adverse effects include [[sepsis]], [[urinary tract infection]], non-melanoma skin cancer ([[basal-cell carcinoma]], [[squamous cell carcinoma]]), [[Leukopenia|low leukocyte count]], [[Lymphocytopenia|low lymphocyte count]], [[interstitial lung disease]], [[tumor lysis syndrome]],<ref>{{cite journal | vauthors = Kaur V, Mehta P, Johnsurd J, Govindarajan R | title = Ibrutinib-associated tumor lysis syndrome in a patient with chronic lymphocytic leukemia | journal = Blood | volume = 124 | issue = 23 | pages = 3503–3505 | date = November 2014 | pmid = 25431479 | doi = 10.1182/blood-2014-08-591875 | doi-access = free }}</ref> [[Hyperuricemia|high uric acid levels]], [[dizziness]], blurred vision, [[atrial fibrillation]], [[subdural hematoma]], nosebleeds, [[Petechia|small bruises from broken blood vessels]], [[Hypertension|high blood pressure]], [[hives]], and skin redness or blushing.<ref name=UKlabel2016>{{cite web|title=UK Ibrutinib label|url=https://www.medicines.org.uk/emc/medicine/29383|publisher=UK Electronic Medicines Compendium|date=25 August 2016|access-date=20 November 2016|archive-date=30 July 2019|archive-url=https://web.archive.org/web/20190730044702/https://www.medicines.org.uk/emc/medicine/29383|url-status=dead}}</ref>


==Pharmacology==
==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]].<ref name=BJCP>{{cite journal | vauthors = deVries R | title = Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults. | journal = Br J Clin Pharmacol | volume = 81 | issue = 2 | pages = 235–45 | year = 2016 | pmid = 26382728| pmc = 4833163 | doi = 10.1111/bcp.12787}}</ref>
Ibrutinib oral bioavailability is 3.9% in a fasting state, 8.4% in a fed state, and 15.9% after consumption of [[grapefruit juice]].<ref name=BJCP>{{cite journal | vauthors = 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 | display-authors = 6 | title = Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults | journal = British Journal of Clinical Pharmacology | volume = 81 | issue = 2 | pages = 235–245 | date = February 2016 | pmid = 26382728 | pmc = 4833163 | doi = 10.1111/bcp.12787 }}</ref>


===Mechanism===
===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.<ref name="Imbruvica EPAR"/>
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.<ref name="Imbruvica EPAR"/>


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.<ref name=JCO>{{cite journal | vauthors = Brown JR | title = Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials | journal = Curr Hematol Malig Rep | volume = 8 | issue = 1 | pages = 1–6 | year = 2013 | pmid = 23296407 | pmc = 3584329 | doi = 10.1007/s11899-012-0147-9 }}</ref>
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.<ref name=JCO>{{cite journal | vauthors = Brown JR | title = Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials | journal = Current Hematologic Malignancy Reports | volume = 8 | issue = 1 | pages = 1–6 | date = March 2013 | pmid = 23296407 | pmc = 3584329 | doi = 10.1007/s11899-012-0147-9 }}</ref>


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.<ref name=Pavlasova2016/> This also leads to a reduction of [[MCL1]] levels (anti-apoptotic protein) in malignant B cells.<ref name=Pavlasova2016/> 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 [[Extracellular signal-regulated kinases|ERK1/2]], [[PI3K/AKT/mTOR pathway|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 ([[B-cell activating factor|BAFF]], [[Interleukin 6|IL-6]], [[Interleukin 4|IL-4]], and [[TNF-α]]), [[fibronectin]] engagement and stromal cell contact.
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.<ref name=Pavlasova2016/> This also leads to a reduction of [[MCL1]] levels (anti-apoptotic protein) in malignant B cells.<ref name=Pavlasova2016/> 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 [[Extracellular signal-regulated kinases|ERK1/2]], [[PI3K/AKT/mTOR pathway|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 ([[B-cell activating factor|BAFF]], [[Interleukin 6|IL-6]], [[Interleukin 4|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 [[chemokine]]s [[CXCL12]] and [[CXCL13]], and inhibit cellular adhesion following stimulation at the [[B-cell receptor]] (BCR).<ref>{{cite journal | vauthors = Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA | title = The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo | journal = Blood | volume = 119 | issue = 5 | pages = 1182–1189 | date = February 2012 | pmid = 22180443 | doi = 10.1182/blood-2011-10-386417 | pmc=4916557}}</ref><ref>{{cite journal | vauthors = de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M | title = The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia | journal = Blood | volume = 119 | issue = 11 | pages = 2590–2594 | date = Mar 2012 | pmid = 22279054 | doi = 10.1182/blood-2011-11-390989 | doi-access = free }}</ref> Additionally, ibrutinib down-modulates the expression of CD20 (target of [[rituximab]]/[[ofatumumab]]) by targeting the [[CXCR4]]/SDF1 axis.<ref name=Pavlasova2016>{{cite journal|last1=Pavlasova|first1=G|display-authors=etal|title=Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis |journal=Blood|date=22 September 2016|volume=128|issue=12|pages=1609–13|pmid=27480113|doi=10.1182/blood-2016-04-709519|pmc=5291297}}</ref>
Ibrutinib has also been reported to reduce chronic lymphocytic leukemia cell [[chemotaxis]] towards the [[chemokine]]s [[CXCL12]] and [[CXCL13]], and inhibit cellular adhesion following stimulation at the [[B-cell receptor]] (BCR).<ref>{{cite journal | vauthors = Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ, O'Brien S, Chiorazzi N, Burger JA | display-authors = 6 | title = The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo | journal = Blood | volume = 119 | issue = 5 | pages = 1182–1189 | date = February 2012 | pmid = 22180443 | pmc = 4916557 | doi = 10.1182/blood-2011-10-386417 }}</ref><ref>{{cite journal | vauthors = de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M | display-authors = 6 | title = The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia | journal = Blood | volume = 119 | issue = 11 | pages = 2590–2594 | date = March 2012 | pmid = 22279054 | doi = 10.1182/blood-2011-11-390989 | doi-access = free }}</ref> Additionally, ibrutinib down-modulates the expression of CD20 (target of [[rituximab]]/[[ofatumumab]]) by targeting the [[CXCR4]]/SDF1 axis.<ref name=Pavlasova2016>{{cite journal | vauthors = 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 | display-authors = 6 | title = Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis | journal = Blood | volume = 128 | issue = 12 | pages = 1609–1613 | date = September 2016 | pmid = 27480113 | pmc = 5291297 | doi = 10.1182/blood-2016-04-709519 }}</ref>
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.
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==
==History==
Ibrutinib was created by scientists at [[Celera Genomics]] as a [[reagent|tool compound]] for studying BTK function; it [[targeted covalent inhibitor|covalently binds its target]] which is ideal for a reagent but generally not considered ideal for drugs.<ref name=Forbes>{{cite news|last1=Shaywitz|first1=David|title=The Wild Story Behind A Promising Experimental Cancer Drug|url=https://www.forbes.com/sites/davidshaywitz/2013/04/05/the-wild-story-behind-a-promising-experimental-cancer-drug/#7ea38d901b9e|work=Forbes|date=April 5, 2013}}</ref>
Ibrutinib was created by scientists at [[Celera Genomics]] as a [[reagent|tool compound]] for studying BTK function; it [[targeted covalent inhibitor|covalently binds its target]] which is ideal for a reagent but generally not considered ideal for drugs.<ref name=Forbes>{{cite news| vauthors = Shaywitz D |title=The Wild Story Behind A Promising Experimental Cancer Drug|url=https://www.forbes.com/sites/davidshaywitz/2013/04/05/the-wild-story-behind-a-promising-experimental-cancer-drug/ |work=Forbes|date=5 April 2013}}</ref>


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.<ref name=Forbes/><ref>{{cite news|last1=Langreth|first1=Robert|last2=Coffey|first2=Brendan|title=Cancer Drug Once Bought for $7 Million May Now Fetch $18 Billion|url=https://www.bloomberg.com/news/articles/2015-02-26/cancer-drug-once-bought-for-7-million-may-now-fetch-18-billion|work=Bloomberg.com|date=26 February 2015}}</ref> 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.<ref>{{cite journal|last1=Sheridan|first1=C|title=Companies in rapid pursuit of Btk immunokinase.|journal=Nature Biotechnology|date=7 March 2012|volume=30|issue=3|pages=199–200|pmid=22398595|doi=10.1038/nbt0312-199|s2cid=205266502}}</ref> Pharmacyclics was acquired by [[AbbVie]] in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.<ref name="WSJ_2016_jan">{{cite web | url=https://www.wsj.com/articles/patients-struggle-with-high-drug-prices-1451557981 | title=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 | work=[[The Wall Street Journal]] | date=1 January 2016 | access-date=31 January 2019 | last=Walker |first=Joseph |url-access=subscription }}</ref>
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.<ref name=Forbes/><ref>{{cite news| vauthors = Langreth R, Coffey B |title=Cancer Drug Once Bought for $7 Million May Now Fetch $18 Billion|url=https://www.bloomberg.com/news/articles/2015-02-26/cancer-drug-once-bought-for-7-million-may-now-fetch-18-billion|work=Bloomberg.com|date=26 February 2015}}</ref> 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.<ref>{{cite journal | vauthors = Sheridan C | title = Companies in rapid pursuit of Btk immunokinase | journal = Nature Biotechnology | volume = 30 | issue = 3 | pages = 199–200 | date = March 2012 | pmid = 22398595 | doi = 10.1038/nbt0312-199 | s2cid = 205266502 }}</ref> Pharmacyclics was acquired by [[AbbVie]] in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.<ref name="WSJ_2016_jan">{{cite web | url=https://www.wsj.com/articles/patients-struggle-with-high-drug-prices-1451557981 | title=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 | work=[[The Wall Street Journal]] | date=1 January 2016 | access-date=31 January 2019 | vauthors = Walker J |url-access=subscription }}</ref>


It was approved by the US [[Food and Drug Administration]] (FDA) on November 13, 2013, for the treatment of [[mantle cell lymphoma]].<ref name="FDA PR 20131113">{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm | archive-url = https://web.archive.org/web/20131113202312/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm | url-status = dead | archive-date = 13 November 2013 | title = FDA approves Imbruvica for rare blood cancer | work = U.S. [[Food and Drug Administration]] (FDA) | date=13 November 2013}} {{PD-notice}}</ref> On February 12, 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL).<ref>{{cite web | title=Imbruvica (ibrutinib) Capsules | website=U.S. [[Food and Drug Administration]] (FDA) | date=8 April 2015 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205552Orig2s000TOC.cfm | access-date=21 April 2020}}</ref><ref name=cancernetwork>{{cite web|last=Azvolinsky |first=Anna|title=FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia|url=http://www.cancernetwork.com/news/fda-approves-ibrutinib-chronic-lymphocytic-leukemia|publisher=Cancer Network|access-date=14 February 2014}}</ref> It was approved for [[Waldenström's macroglobulinemia]] in 2015.<ref name="FDA PR 20150129">{{cite press release|title=FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm |archive-url=https://web.archive.org/web/20150201035442/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm |url-status=dead |archive-date=February 1, 2015 |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=January 29, 2015}} {{PD-notice}}</ref><ref>{{cite web | title=Imbruvica (ibrutinib) Now Approved to Treat Waldenstrom's Macroglobulinemia in Europe | website=AbbVie | date=10 July 2015 | url=https://news.abbvie.com/news/imbruvica-ibrutinib-now-approved-to-treat-waldenstroms-macroglobulinemia-in-europe.htm | access-date=21 April 2020}}</ref>
It was approved by the US [[Food and Drug Administration]] (FDA) in November 2013, for the treatment of [[mantle cell lymphoma]].<ref name="FDA PR 20131113">{{cite press release | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm | archive-url = https://web.archive.org/web/20131113202312/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm | url-status = dead | archive-date = 13 November 2013 | title = FDA approves Imbruvica for rare blood cancer | work = U.S. [[Food and Drug Administration]] (FDA) | date=13 November 2013}} {{PD-notice}}</ref> In February 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL).<ref>{{cite web | title=Imbruvica (ibrutinib) Capsules | website=U.S. [[Food and Drug Administration]] (FDA) | date=8 April 2015 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205552Orig2s000TOC.cfm | access-date=21 April 2020}}</ref><ref name=cancernetwork>{{cite web| vauthors = Azvolinsky A |title=FDA Approves Ibrutinib for Chronic Lymphocytic Leukemia|url=http://www.cancernetwork.com/news/fda-approves-ibrutinib-chronic-lymphocytic-leukemia|publisher=Cancer Network|access-date=14 February 2014|archive-date=22 February 2014|archive-url=https://web.archive.org/web/20140222170346/http://www.cancernetwork.com/news/fda-approves-ibrutinib-chronic-lymphocytic-leukemia|url-status=dead}}</ref> It was approved for [[Waldenström's macroglobulinemia]] in 2015.<ref name="FDA PR 20150129">{{cite press release|title=FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm |archive-url=https://web.archive.org/web/20150201035442/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm |url-status=dead |archive-date=1 February 2015 |publisher=U.S. [[Food and Drug Administration]] (FDA) |date=29 January 2015}} {{PD-notice}}</ref><ref>{{cite web | title=Imbruvica (ibrutinib) Now Approved to Treat Waldenstrom's Macroglobulinemia in Europe | website=AbbVie | date=10 July 2015 | url=https://news.abbvie.com/news/imbruvica-ibrutinib-now-approved-to-treat-waldenstroms-macroglobulinemia-in-europe.htm | access-date=21 April 2020 | archive-date=13 July 2020 | archive-url=https://web.archive.org/web/20200713042931/https://news.abbvie.com/news/imbruvica-ibrutinib-now-approved-to-treat-waldenstroms-macroglobulinemia-in-europe.htm | url-status=dead }}</ref>


In March 2015, Pharmacyclics and [[AbbVie]] agreed that Abbvie would acquire Pharmacyclics for $21 billion;<ref>{{cite news|last1=Rockoff|first1=Jonathan D.|last2=Loftus|first2=Peter|title=AbbVie to Buy Pharmacyclics in $21 Billion Deal|url=https://www.wsj.com/articles/abbvie-to-buy-pharmacyclics-in-21-billion-deal-1425528086|work=[[The Wall Street Journal]]|date=5 March 2015 |url-access=subscription }}</ref> the deal was completed that May.<ref>{{cite news|last1=Sachdev|first1=Ameet|title=AbbVie closes $21 billion deal for Pharmacyclics|url=http://www.chicagotribune.com/business/ct-abbvie-pharmacyclics-0527-biz-20150526-story.html|work=Chicago Tribune|date=May 26, 2015}}</ref>
In March 2015, Pharmacyclics and [[AbbVie]] agreed that Abbvie would acquire Pharmacyclics for $21 billion;<ref>{{cite news| vauthors = Rockoff JD, Loftus P |title=AbbVie to Buy Pharmacyclics in $21 Billion Deal|url=https://www.wsj.com/articles/abbvie-to-buy-pharmacyclics-in-21-billion-deal-1425528086|work=[[The Wall Street Journal]]|date=5 March 2015 |url-access=subscription }}</ref> the deal was completed that May.<ref>{{cite news| vauthors = Sachdev A |title=AbbVie closes $21 billion deal for Pharmacyclics|url=http://www.chicagotribune.com/business/ct-abbvie-pharmacyclics-0527-biz-20150526-story.html|work=Chicago Tribune|date=26 May 2015}}</ref>


In March 2016, a new indication for ibrutinib was approved in the United States for patients with chronic lymphocytic leukemia (CLL).<ref>{{cite press release | title=Imbruvica (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia | website=AbbVie | date=4 March 2016 | url=https://news.abbvie.com/news/imbruvica-ibrutinib-approved-by-us-fda-for-first-line-treatment-chronic-lymphocytic-leukemia.htm | access-date=21 April 2020}}</ref>
In March 2016, a new indication for ibrutinib was approved in the United States for patients with chronic lymphocytic leukemia (CLL).<ref>{{cite press release | title=Imbruvica (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia | website=AbbVie | date=4 March 2016 | url=https://news.abbvie.com/news/imbruvica-ibrutinib-approved-by-us-fda-for-first-line-treatment-chronic-lymphocytic-leukemia.htm | access-date=21 April 2020 | archive-date=22 April 2020 | archive-url=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 | url-status=dead }}</ref>


In May 2016, a new indication for ibrutinib was approved in the United States for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).<ref>{{cite press release | title=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 | website=AbbVie | date=9 May 2016 | url=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 | access-date=21 April 2020}}</ref>
In May 2016, a new indication for ibrutinib was approved in the United States for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).<ref>{{cite press release | title=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 | website=AbbVie | date=9 May 2016 | url=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 | access-date=21 April 2020 | archive-date=22 April 2020 | archive-url=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 | url-status=dead }}</ref>


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.<ref>{{cite press release | title=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 | website=AbbVie | date=19 January 2017 | url=https://news.abbvie.com/news/press-releases/us-fda-approves-imbruvica-ibrutinib-as-first-treatment-specifically-indicated-for-relapsedrefractory-marginal-zone-lymphoma-mzl--rare-type-non-hodgkins-lymphoma.htm | access-date=21 April 2020}}</ref>
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.<ref>{{cite press release | title=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 | website=AbbVie | date=19 January 2017 | url=https://news.abbvie.com/news/press-releases/us-fda-approves-imbruvica-ibrutinib-as-first-treatment-specifically-indicated-for-relapsedrefractory-marginal-zone-lymphoma-mzl--rare-type-non-hodgkins-lymphoma.htm | access-date=21 April 2020}}</ref>
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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).<ref name="FDA 20200421">{{cite web | title=FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia | website=U.S. [[Food and Drug Administration]] (FDA)| date=21 April 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ibrutinib-plus-rituximab-chronic-lymphocytic-leukemia | access-date=21 April 2020}} {{PD-notice}}</ref> 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.<ref name="FDA 20200421" />
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).<ref name="FDA 20200421">{{cite web | title=FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia | website=U.S. [[Food and Drug Administration]] (FDA)| date=21 April 2020 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ibrutinib-plus-rituximab-chronic-lymphocytic-leukemia | access-date=21 April 2020}} {{PD-notice}}</ref> 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.<ref name="FDA 20200421" />


== Society and culture ==
==Cost==
=== Economics ===
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 discontinued the capsule formulation. This caused an outcry as it was perceived to triple the cost of the drug to the average patient.<ref>{{cite news | vauthors = Johnson CY |url=https://www.washingtonpost.com/news/wonk/wp/2018/04/18/science-hinted-that-cancer-patients-could-take-less-of-a-148000-a-year-drug-the-company-tripled-the-price-of-a-pill/ |title=Science hinted that cancer patients could take less of a $148,000-a-year drug. Its maker tripled the price of a pill. |newspaper=[[The Washington Post]] |date=18 April 2018 |access-date=19 April 2018 }}</ref>


[[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.<ref>{{cite news |last=Johnson |first=Carolyn Y. |url=https://www.washingtonpost.com/news/wonk/wp/2018/04/18/science-hinted-that-cancer-patients-could-take-less-of-a-148000-a-year-drug-the-company-tripled-the-price-of-a-pill/ |title=Science hinted that cancer patients could take less of a $148,000-a-year drug. Its maker tripled the price of a pill. |work=[[The Washington Post]] |date=2018-04-18 |access-date=2018-04-19 }}</ref> 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.<ref>{{cite news | vauthors = Johnson CY |url=https://www.washingtonpost.com/news/wonk/wp/2018/05/15/after-outcry-drugmakers-decide-not-to-triple-the-price-of-a-cancer-pill/ |title=After outcry, drugmakers decide not to triple the price of a cancer pill.|newspaper=[[The Washington Post]] |date=15 May 2018 |access-date=13 June 2018 }}</ref>


⚫
Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme in 2018.<ref>{{cite web |title=MIL-OSI Australia: $250 million investment in life changing cancer medicines – ForeignAffairs.co.nz |url=https://foreignaffairs.co.nz/2018/07/16/mil-osi-australia-250-million-investment-in-life-changing-cancer-medicines/ |website=Foreignaffairs.co.nz |access-date=20 July 2018 |date=16 July 2018 |archive-date=20 July 2018 |archive-url=https://web.archive.org/web/20180720080941/https://foreignaffairs.co.nz/2018/07/16/mil-osi-australia-250-million-investment-in-life-changing-cancer-medicines/ |url-status=dead }}</ref>
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.<ref>{{cite news | last=Johnson |first=Carolyn Y. |url=https://www.washingtonpost.com/news/wonk/wp/2018/05/15/after-outcry-drugmakers-decide-not-to-triple-the-price-of-a-cancer-pill/ |title=After outcry, drugmakers decide not to triple the price of a cancer pill.|work=[[The Washington Post]] |date=2018-05-15 |access-date=2018-06-13 }}</ref>

⚫
Ibrutinib was added to the Australian Pharmaceutical Benefits Scheme in 2018.<ref>{{cite web |title=MIL-OSI Australia: $250 million investment in life changing cancer medicines – ForeignAffairs.co.nz |url=https://foreignaffairs.co.nz/2018/07/16/mil-osi-australia-250-million-investment-in-life-changing-cancer-medicines/ |website=Foreignaffairs.co.nz |access-date=20 July 2018 |date=16 July 2018}}</ref>


Generic ibrutinib was added to the Indian Pharmaceutical Benefits Scheme in 2020.<ref>{{cite web |title=Cost-effectiveness Ibrutinib [Imbruvica] In India, USA, UK, And Australia – Medixocentre.com |url=https://www.medixocentre.com/ibrutinib-cost |website=Medixocentre.com |access-date=15 February 2020 |date=10 February 2020}}</ref>
Generic ibrutinib was added to the Indian Pharmaceutical Benefits Scheme in 2020.<ref>{{cite web |title=Cost-effectiveness Ibrutinib [Imbruvica] In India, USA, UK, And Australia – Medixocentre.com |url=https://www.medixocentre.com/ibrutinib-cost |website=Medixocentre.com |access-date=15 February 2020 |date=10 February 2020}}</ref>

Imbruvica was named in 2023 as one of the first 10 drugs to be subjected to [[Medicare (United States)|Medicare]] price negotiations under the [[Inflation Reduction Act]].<ref>{{Cite web |date=2023-08-29 |title=CMS Releases List of 10 Drugs Subject to Price Negotiation Under IRA |url=https://www.ajmc.com/view/cms-releases-list-of-10-drugs-subject-to-price-negotiation-under-ira |access-date=2024-03-17 |website=AJMC |language=en}}</ref>


== References ==
== References ==
{{reflist}}
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Nocco S, Andriano TM, Bose A, Chilov M, Godwin K, Dranitsaris G, Wu S, Lacouture ME, Roeker LE, Mato AR, Markova A | display-authors = 6 | title = Ibrutinib-associated dermatologic toxicities: A systematic review and meta-analysis | journal = Critical Reviews in Oncology/Hematology | volume = 174 | issue = | pages = 103696 | date = June 2022 | pmid = 35523374 | doi = 10.1016/j.critrevonc.2022.103696 | s2cid = 248554326 }}
* {{cite journal | vauthors = Ran F, Liu Y, Wang C, Xu Z, Zhang Y, Liu Y, Zhao G, Ling Y | display-authors = 6 | title = Review of the development of BTK inhibitors in overcoming the clinical limitations of ibrutinib | journal = European Journal of Medicinal Chemistry | volume = 229 | issue = | pages = 114009 | date = February 2022 | pmid = 34839996 | doi = 10.1016/j.ejmech.2021.114009 | s2cid = 244502431 }}
{{refend}}


== External links ==
== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/ibrutinib | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Ibrutinib }}
* [https://www.cancer.gov/publications/dictionaries/cancer-drug/def/ibrutinib Ibrutinib], [[National Cancer Institute]] Drug Dictionary
* [https://www.cancer.gov/publications/dictionaries/cancer-drug/def/ibrutinib Ibrutinib], [[National Cancer Institute]] Drug Dictionary


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[[Category:AbbVie brands]]
[[Category:Drugs developed by AbbVie]]
[[Category:Acrylamides]]
[[Category:Acrylamides]]
[[Category:Breakthrough therapy]]
[[Category:Drugs developed by Johnson & Johnson]]
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[[Category:Tyrosine kinase inhibitors]]
[[Category:Tyrosine kinase inhibitors]]
[[Category:World Health Organization essential medicines]]
[[Category:World Health Organization essential medicines]]
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[[Category:Small-molecule drugs]]

Latest revision as of 21:22, 16 August 2024

Ibrutinib
Clinical data
Trade namesImbruvica, others
Other namesPCI-32765, CRA-032765
AHFS/Drugs.comMonograph
MedlinePlusa614007
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding97.3%
MetabolismHepatic (CYP3A & CYP2D6)
Elimination half-life4–6 hours
ExcretionFeces (80%), urine (10%)
Identifiers
  • 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.232.543 Edit this at Wikidata
Chemical and physical data
FormulaC25H24N6O2
Molar mass440.507 g·mol−1
3D model (JSmol)
  • 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=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 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.[6][7] 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.[8]

It is on the World Health Organization's List of Essential Medicines.[9]

Medical uses

[edit]

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).[5][6][7][10][11][12][13][14]

Adverse effects

[edit]

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,[15] 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

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Ibrutinib oral bioavailability is 3.9% in a fasting state, 8.4% in a fed state, and 15.9% after consumption of grapefruit juice.[16]

Mechanism

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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.[7]

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.[17]

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.[18] This also leads to a reduction of MCL1 levels (anti-apoptotic protein) in malignant B cells.[18] 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).[19][20] Additionally, ibrutinib down-modulates the expression of CD20 (target of rituximab/ofatumumab) by targeting the CXCR4/SDF1 axis.[18] 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

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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.[21]

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.[21][22] 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.[23] Pharmacyclics was acquired by AbbVie in May 2015, and Abbvie projected global sales of US$1 billion in 2016 and $5 billion in 2020.[24]

It was approved by the US Food and Drug Administration (FDA) in November 2013, for the treatment of mantle cell lymphoma.[10] In February 2014, the FDA expanded the approved use of ibrutinib to chronic lymphocytic leukemia (CLL).[25][26] It was approved for Waldenström's macroglobulinemia in 2015.[11][27]

In March 2015, Pharmacyclics and AbbVie agreed that Abbvie would acquire Pharmacyclics for $21 billion;[28] the deal was completed that May.[29]

In March 2016, a new indication for ibrutinib was approved in the United States for patients with chronic lymphocytic leukemia (CLL).[30]

In May 2016, a new indication for ibrutinib was approved in the United States for chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).[31]

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.[32]

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.[12][13][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.[37]

Society and culture

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Economics

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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]

References

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  32. ^ "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. Retrieved 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 (Press release). 2 August 2017. Retrieved 21 April 2020.
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  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 (Press release). 28 January 2019. Retrieved 21 April 2020.
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Further reading

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