Singapore Drugs Database

Indication

Ibrutinib acquired an accelerated approval for the treatment of mantle cell lymphoma who have received at least one prior therapy.[FDA label] Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma that develops in the outer edge of a lymph node. MCL is usually diagnosed at late stages and it is easily spread into bone marrow, spleen, liver and gastrointestinal tract.[L1929] Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL) who have at least one prior therapy.[FDA label] CLL is a type of cancer caused by an overproduction of lymphocytes by the bone marrow. Some of the symptoms include swollen lymph nodes and tiredness.[L1931] Ibrutinib is indicated for the treatment of chronic lymphocytic leukemia (CLL) with 17p deletion.[FDA label] CLL with 17p is a type of leukemia in which a deletion in 17p disrupts the tumor suppressor p53 by deleting one allele of the TP53 gene. The remaining allele is mainly inactivated and thus, this type of leukemia is unresponsive to p53-dependent treatments.[A32305] Ibrutinib is indicated for the treatment of patients with Waldenstrom's Macroglobulinemia (WM).[FDA label] WM, also called lymphoplasmacytic lymphoma, is a type of non-Hodgkin lymphoma in which the cancer cells make large amounts of macroglobulin. The macroglobulin is a monoclonal protein that corresponds to the type of IgM antibodies and the unrestricted formation of this protein causes typical symptoms such as excessive bleeding and effects in vision and nervous system.[L1934]

Mechanism of Action

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). It forms a covalent bond with a cysteine residue in the active site of BTK (Cys481), leading to its inhibition. The inhibition of BTK plays a role in the B-cell receptor signaling and thus, the presence of ibrutinib prevents the phosphorylation of downstream substrates such as PLC-γ.[A32306]

Pharmacokinetics

Absorption

Ibrutinib is rapidly absorbed after oral administration and it presents a Cmax, tmax and AUC of approximately 35 ng/ml, 1-2 hour and 953 mg.h/ml respectively.[T148]

Distribution

The volume of distribution at steady-state of ibrutinib is in approximately 10,000 L.[T148]

Metabolism

Three metabolic pathways have been identified according to the possible metabolites. These pathways are the hydroxylation of the phenyl group (M35), the opening of the piperidine with a reduction of the primary alcohol (M34) and the oxidation to a carboxylic acid and epoxidation of the ethylene followed by a hydrolysis to the formation of dihydrodiol (PCI-45227). The latter metabolite presents also 15 times lower inhibitory activity against BTK. The metabolism of ibrutinib is mainly performed by CYP3A5 and CYP3A4. and in a minor extent it is seen to be performed by CYP2D6.[A7663]

Elimination

Clearance

In patients with normal renal function, the clearance rate is in the range of 112-159 ml/min.[A7663]

Toxicity

Ibrutinib was not showed to present a mutagenic potential in bacterial assays, nor clastogenic in chromosome aberration assays in mammalian cells or in bone marrow micronucleus assays in mice. Carcinogenicity or effects on fertility have not been determined.[FDA label]

Active Ingredient/Synonyms

1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one | Ibrutinib |