ibrutinib

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Ligands
ibrutinib

GtoPdb Ligand ID: 6912

Synonyms: Imbruvica® | PCI-32765

ibrutinib is an approved drug (FDA (2013), EMA (2014))

Compound class: Synthetic organic

Comment: Ibrutinib is a clinically used inhibitor of Bruton's tyrosine kinase. It was originally approved with breakthrough therapy designation through the FDA's accelerated approval program.

View interactive charts of activity data across species

View more information in the IUPHAR Pharmacology Education Project: ibrutinib

ibrutinib is commercially available from our sponsors

2D Structure

Physico-chemical Properties

Hydrogen bond acceptors	6
Hydrogen bond donors	1
Rotatable bonds	6
Topological polar surface area	99.16
Molecular weight	440.2
XLogP	4.12
No. Lipinski's rules broken	0

SMILES / InChI / InChIKey

Canonical SMILES	C=CC(=O)N1CCCC(C1)n1nc(c2c1ncnc2N)c1ccc(cc1)Oc1ccccc1
Isomeric SMILES	C=CC(=O)N1CCC[C@H](C1)n1nc(c2c1ncnc2N)c1ccc(cc1)Oc1ccccc1
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
InChI Key	XYFPWWZEPKGCCK-GOSISDBHSA-N

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Summary of Clinical Use
Ibrutinib is approved to treat patients with mantle cell lymphoma (MCL), a rare and aggressive type of leukemia, especially patients with MCL who have received at least one prior therapy. In Feb 2014 ibrutinib was granted US FDA approval for treating chronic lymphocytic leukemia (CLL), as with MCL, this is only indicated for patients who have received at least one prior therapy. In February 2015, the US FDA expanded approval to include the treatment of Waldenström's macroglobulinemia (WM), which is a form of type of non-Hodgkin's lymphoma. Approval was granted based on the outcome of clinical trial NCT01614821 which indicated that the drug can offer a substantial improvement over contemporary therapies. In August 2017, the FDA expanded approval to include treatment of chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy (e.g. first-line corticosteroid therapy). This approval followed results from clinical trial NCT02195869. The recommended dose of ibrutinib for cGVHD is 420 mg, orally once daily.

Summary of Clinical Use

Ibrutinib is approved to treat patients with mantle cell lymphoma (MCL), a rare and aggressive type of leukemia, especially patients with MCL who have received at least one prior therapy. In Feb 2014 ibrutinib was granted US FDA approval for treating chronic lymphocytic leukemia (CLL), as with MCL, this is only indicated for patients who have received at least one prior therapy. In February 2015, the US FDA expanded approval to include the treatment of Waldenström's macroglobulinemia (WM), which is a form of type of non-Hodgkin's lymphoma. Approval was granted based on the outcome of clinical trial NCT01614821 which indicated that the drug can offer a substantial improvement over contemporary therapies.
In August 2017, the FDA expanded approval to include treatment of chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy (e.g. first-line corticosteroid therapy). This approval followed results from clinical trial NCT02195869. The recommended dose of ibrutinib for cGVHD is 420 mg, orally once daily.

Mechanism Of Action and Pharmacodynamic Effects
Bruton's tyrosine kinase (BTK) is a key mediator of critical B-cell pro-survival mechanisms, including regulation of B-cell apoptosis, cell adhesion, and lymphocyte migration and traffiking to lymphoid tissue. Ibrutinib inhibits BTK by covalently binding to cysteine-481 close to the ATP binding domain of the kinase. By inhibiting this kinase, ibrutinib promotes malignant B-cell apoptosis, inhibits proliferation and prevents these cells from responding to survival stimuli present in the microenvironment.

Mechanism Of Action and Pharmacodynamic Effects

Bruton's tyrosine kinase (BTK) is a key mediator of critical B-cell pro-survival mechanisms, including regulation of B-cell apoptosis, cell adhesion, and lymphocyte migration and traffiking to lymphoid tissue. Ibrutinib inhibits BTK by covalently binding to cysteine-481 close to the ATP binding domain of the kinase. By inhibiting this kinase, ibrutinib promotes malignant B-cell apoptosis, inhibits proliferation and prevents these cells from responding to survival stimuli present in the microenvironment.

Pharmacokinetics
Absorption/Distribution
Peak plasma concentration (T_max) is reached approximately 2 hours following oral dose and is independent of the size of the dose administered. Total exposure following oral dose is proportional to the dose administered [1].
Elimination
Terminal half-life is unchanged in relation to the dose administered (7.8±3.6 hours with 420 mg per day and 8.1±3.4 hours with 840 mg per day) [1].
Population pharmacokinetics
There is no evidence to suggest that the effectiveness of ibrutinib is altered in elderly patients. The effectiveness of ibrutinib in the pediatric population has not been assessed.

Pharmacokinetics

Absorption/Distribution

Peak plasma concentration (T_max) is reached approximately 2 hours following oral dose and is independent of the size of the dose administered. Total exposure following oral dose is proportional to the dose administered [1].

Elimination

Terminal half-life is unchanged in relation to the dose administered (7.8±3.6 hours with 420 mg per day and 8.1±3.4 hours with 840 mg per day) [1].

Population pharmacokinetics

There is no evidence to suggest that the effectiveness of ibrutinib is altered in elderly patients. The effectiveness of ibrutinib in the pediatric population has not been assessed.