Ibrutinib

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]

Ibrutinib

Clinical data
Trade names	Imbruvica, others
Other names	PCI-32765, CRA-032765
AHFS/Drugs.com	Monograph
MedlinePlus	a614007
License data	US DailyMed: Ibrutinib
Pregnancy category	AU: D^[1]
Routes of administration	By mouth
ATC code	L01EL01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)^[2] CA: ℞-only^[3] UK: POM (Prescription only)^[4]^[5] US: ℞-only^[6] EU: Rx-only^[7] In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	97.3%
Metabolism	Hepatic (CYP3A & CYP2D6)
Elimination half-life	4–6 hours
Excretion	Feces (80%), urine (10%)
Identifiers
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
CAS Number	936563-96-1
PubChem CID	24821094
IUPHAR/BPS	6912
DrugBank	DB09053
ChemSpider	26637187
UNII	1X70OSD4VX
KEGG	D10223
ChEBI	CHEBI:76612
ChEMBL	ChEMBL1873475
PDB ligand	1E8 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID60893450
ECHA InfoCard	100.232.543
Chemical and physical data
Formula	C25H24N6O2
Molar mass	440.507 g·mol^−1
3D model (JSmol)	Interactive image
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

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

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

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.^[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

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

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 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.^[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

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

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]

References

1. "Ibrutinib (Imbruvica) Use During Pregnancy". Drugs.com. 3 December 2019. Retrieved 28 March 2020.
2. "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
3. "Regulatory Decision Summary for Imbruvica". Drug and Health Products Portal. 4 August 2023. Retrieved 2 April 2024.
4. "Imbruvica 140 mg Film-Coated Tablets - Summary of Product Characteristics (SmPC)". (emc). 16 January 2020. Retrieved 28 March 2020.
5. . UK Electronic Medicines Compendium. 25 August 2016. Archived from the original on 30 July 2019. Retrieved 20 November 2016.
6. "Imbruvica- ibrutinib capsule Imbruvica- ibrutinib tablet, film coated". DailyMed. 8 April 2020. Retrieved 21 April 2020.
7. "Imbruvica EPAR". European Medicines Agency (EMA). 8 July 2021. Retrieved 14 July 2021.
8. Xiao L, Salem JE, Clauss S, Hanley A, Bapat A, Hulsmans M, et al. (December 2020). "Ibrutinib-Mediated Atrial Fibrillation Attributable to Inhibition of C-Terminal Src Kinase". Circulation. 142 (25): 2443–2455. doi:10.1161/CIRCULATIONAHA.120.049210. PMC 9661397. PMID 33092403.
9. 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.
10. . U.S. Food and Drug Administration (FDA) (Press release). 13 November 2013. Archived from the original on 13 November 2013.   This article incorporates text from this source, which is in the public domain.
11. (Press release). U.S. Food and Drug Administration (FDA). 29 January 2015. Archived from the original on 1 February 2015.   This article incorporates text from this source, which is in the public domain.
12. "FDA approves treatment for chronic graft versus host disease" (Press release). U.S. Food and Drug Administration (FDA). 2 August 2017. Retrieved 28 March 2020.   This article incorporates text from this source, which is in the public domain.
13. "FDA expands ibrutinib indications to chronic GVHD". U.S. Food and Drug Administration (FDA). 2 August 2017. Retrieved 21 April 2020.
14. "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. Retrieved 24 August 2022.
15. 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): 3503–3505. doi:10.1182/blood-2014-08-591875. PMID 25431479.
16. de Vries R, Smit JW, Hellemans P, Jiao J, Murphy J, Skee D, et al. (February 2016). "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. doi:10.1111/bcp.12787. PMC 4833163. PMID 26382728.
17. Brown JR (March 2013). "Ibrutinib (PCI-32765), the first BTK (Bruton's tyrosine kinase) inhibitor in clinical trials". Current Hematologic Malignancy Reports. 8 (1): 1–6. doi:10.1007/s11899-012-0147-9. PMC 3584329. PMID 23296407.
18. Pavlasova G, Borsky M, Seda V, Cerna K, Osickova J, Doubek M, et al. (September 2016). "Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis". Blood. 128 (12): 1609–1613. doi:10.1182/blood-2016-04-709519. PMC 5291297. PMID 27480113.
19. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. (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.
20. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. (March 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.
21. Shaywitz D (5 April 2013). "The Wild Story Behind A Promising Experimental Cancer Drug". Forbes.
22. Langreth R, Coffey B (26 February 2015). "Cancer Drug Once Bought for $7 Million May Now Fetch $18 Billion". Bloomberg.com.
23. Sheridan C (March 2012). "Companies in rapid pursuit of Btk immunokinase". Nature Biotechnology. 30 (3): 199–200. doi:10.1038/nbt0312-199. PMID 22398595. S2CID 205266502.
24. Walker J (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. Retrieved 31 January 2019.
25. "Imbruvica (ibrutinib) Capsules". U.S. Food and Drug Administration (FDA). 8 April 2015. Retrieved 21 April 2020.
26. Azvolinsky A. . Cancer Network. Archived from the original on 22 February 2014. Retrieved 14 February 2014.
27. "Imbruvica (ibrutinib) Now Approved to Treat Waldenstrom's Macroglobulinemia in Europe". AbbVie. 10 July 2015. Retrieved 21 April 2020.
28. Rockoff JD, Loftus P (5 March 2015). "AbbVie to Buy Pharmacyclics in $21 Billion Deal". The Wall Street Journal.
29. Sachdev A (26 May 2015). "AbbVie closes $21 billion deal for Pharmacyclics". Chicago Tribune.
30. "Imbruvica (ibrutinib) Approved by U.S. FDA for the First-line Treatment of Chronic Lymphocytic Leukemia". AbbVie (Press release). 4 March 2016. Retrieved 21 April 2020.
31. "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. Retrieved 21 April 2020.
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.
34. "Drug Approval Package: Imbruvica (ibrutinib)". U.S. Food and Drug Administration (FDA). 26 October 2018. Retrieved 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 (Press release). 27 August 2018. Retrieved 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 (Press release). 28 January 2019. Retrieved 21 April 2020.
37. "FDA approves ibrutinib plus rituximab for chronic lymphocytic leukemia". U.S. Food and Drug Administration (FDA). 21 April 2020. Retrieved 21 April 2020.   This article incorporates text from this source, which is in the public domain.
38. Johnson CY (18 April 2018). "Science hinted that cancer patients could take less of a $148,000-a-year drug. Its maker tripled the price of a pill". The Washington Post. Retrieved 19 April 2018.
39. Johnson CY (15 May 2018). "After outcry, drugmakers decide not to triple the price of a cancer pill". The Washington Post. Retrieved 13 June 2018.
40. . Foreignaffairs.co.nz. 16 July 2018. Archived from the original on 20 July 2018. Retrieved 20 July 2018.
41. "Cost-effectiveness Ibrutinib [Imbruvica] In India, USA, UK, And Australia – Medixocentre.com". Medixocentre.com. 10 February 2020. Retrieved 15 February 2020.
42. "CMS Releases List of 10 Drugs Subject to Price Negotiation Under IRA". AJMC. 29 August 2023. Retrieved 17 March 2024.

Further reading

• Nocco S, Andriano TM, Bose A, Chilov M, Godwin K, Dranitsaris G, et al. (June 2022). "Ibrutinib-associated dermatologic toxicities: A systematic review and meta-analysis". Critical Reviews in Oncology/Hematology. 174: 103696. doi:10.1016/j.critrevonc.2022.103696. PMID 35523374. S2CID 248554326.
• Ran F, Liu Y, Wang C, Xu Z, Zhang Y, Liu Y, et al. (February 2022). "Review of the development of BTK inhibitors in overcoming the clinical limitations of ibrutinib". European Journal of Medicinal Chemistry. 229: 114009. doi:10.1016/j.ejmech.2021.114009. PMID 34839996. S2CID 244502431.

External links

• Ibrutinib, National Cancer Institute Drug Dictionary