Mechanism of Action
- Abnormal B-cell receptor (BCR) signaling is a key mechanism of disease progression in B-cell malignancy. The BCR is a complex consisting of a membrane bound immunoglobulin (Ig) coupled with heterodimers of the transmembrane proteins CD79a (Igalpha) and CD79b (Igbeta). BTK is a non-receptor tyrosine kinase of the Tec-kinase family. It is primarily expressed in B cells and is of central importance in BCR signaling.
- Ibrutinib works by covalent irreversible binding of Cystein residue 481 in the
kinase domain of BTK. Only about 10 other kinases contain a homologous cystein residue and thus are prone to irreversible inhibition by ibrutinib. These include BMX, EGFR, HER2 and nHer4, BLK and JAK3.
- Ibrutinib is absorbed after oral administration with a median T max of 1 to 2 hours.
- Administration with food increases ibrutinib exposure approximately 2-fold compared with administration after overnight fasting.
- Metabolism is the main route of elimination for ibrutinib.
- It is metabolized to several metabolites primarily by cytochrome P450, CYP3A, and to a minor extent by CYP2D6.
- The half-life of ibrutinib is 4 to 6 hours.
- Ibrutinib, mainly in the form of metabolites, is eliminated primarily via faeces.
- Relapsed Chronic Lymphocytic Leukemia (CLL)
- Mantle cell lymphoma (MCL) who have received at least one prior therapy.
- 560 mg (four 140 mg capsules) orally once daily at approximately the same time each day.
- Swallow the capsules whole with water.
- Do not open, break, or chew the capsules.
- Missed Dose:
- If a dose is not taken at the scheduled time, it can be taken on the same day as soon as possible.
- Extra capsules should not be taken to make up for the missed dose.
- 140 mg capsules
Interrupt therapy for any
- Grade 3 or greater non-hematological,
- Grade 3 or greater neutropenia with infection or fever,
- Grade 4 hematological toxicities.
- musculoskeletal pain,
- peripheral edema,
- upper respiratory tract infection,
- abdominal pain,
- vomiting and
- decreased appetite.
- 5%of patients with MCL had Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, and hematuria).
- Overall, bleeding events of any grade occurred in 48% of patients treated with 560 mg daily.
- Withhold ibrutinib for at least 3 to 7 days pre and post-surgery.
- Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients
Second Primary Malignancies