Ibrutinib-Mechanism of Action, Indications, Dose, Side Effects

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Ibrutinib

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.

Pharmacokinetics

  • 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.

Indications

Dosage

  • 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.

Availability

  • 140 mg capsules

Dose Modifications

Interrupt therapy for any

  • Grade 3 or greater non-hematological,
  • Grade 3 or greater neutropenia with infection or fever,
  • Grade 4 hematological toxicities.

Adverse Reactions/Toxicities

Most common

  • thrombocytopenia,
  • diarrhea,
  • neutropenia,
  • anemia,
  • fatigue,
  • musculoskeletal pain,
  • peripheral edema,
  • upper respiratory tract infection,
  • nausea,
  • bruising,
  • dyspnea,
  • constipation,
  • rash,
  • abdominal pain,
  • vomiting and
  • decreased appetite.

Hemorrhage

  • 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.

Infections

Myelosuppression

  • Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients

Renal Toxicity

Second Primary Malignancies

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