Ibrutinib

Ibrutinib belongs to a class of drugs called Bruton's tyrosine kinase inhibitors. It is primarily used for the treatment of certain B-cell malignancies, including Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, and Mantle Cell Lymphoma in relapsed or refractory cases. Additionally, it is indicated for the treatment of Waldenström’s Macroglobulinemia, Marginal Zone Lymphoma, and Chronic Graft-versus-Host Disease. Since its initial approval, Ibrutinib has played a significant role in the management of these conditions by blocking BTK signaling, thereby disrupting malignant B-cell growth and survival.

Ibrutinib was first approved by the U.S. Food and Drug Administration (FDA) in 2013 for the treatment of Mantle Cell Lymphoma in patients who had received at least one prior therapy. Since its initial approval, its indications have expanded to include several B-cell malignancies, such as Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Waldenström’s Macroglobulinemia, and Marginal Zone In 2017, the FDA approved Ibrutinib for the treatment of chronic Graft-versus-Host Disease in patients who had failed prior lines of therapy, making it the first BTK inhibitor approved for a non-cancerous condition. Due to its efficacy in targeting B-cell receptor signaling pathways, Ibrutinib has been approved in multiple countries and has become a widely used therapy for various hematologic disorders.

BRAND NAMES

Imbruvica: Imbruvica capsule is used to treat mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). It is also indicated for patients with CLL who have received at least one prior therapy.

MECHANISM OF ACTION

Ibrutinib is an irreversible and selective Bruton’s tyrosine kinase (BTK) inhibitor that blocks B-cell receptor (BCR) signaling, which is essential for the survival and proliferation of malignant B-cells. By binding covalently to Cysteine-481 in the active site of BTK, it permanently inhibits BTK activity, thereby disrupting tumor growth, reducing B-cell adhesion, and preventing migration to lymphoid tissues. In addition to BTK, Ibrutinib also partially inhibits other kinases, such as ITK, EGFR, and TEC family kinases, which contribute to immune modulation and cancer progression.

PHARMACOKINETICS

Absorption

Ibrutinib is rapidly absorbed after oral administration.
Peak plasma concentration (Cmax) is reached in 1 to 2 hours.
Food effect: Taking Ibrutinib with a high-fat meal increases its absorption (higher Cmax and AUC).

Distribution

Ibrutinib has a high volume of distribution (Vd ~10,000 L), indicating extensive tissue penetration.
It is highly protein-bound (~97%), mainly to albumin.

Metabolism

Hepatic metabolism: Ibrutinib is extensively metabolized in the liver via CYP3A4 (major) and CYP2D6 (minor).
Its major active metabolite, PCI-45227, has similar BTK inhibitory activity but is present at lower concentrations.

Elimination

Ibrutinib has a half-life of ~4 to 6 hours, but its effects are prolonged due to irreversible BTK binding.
It is primarily excreted in feces (~80%) and to a lesser extent in urine (~10%).

DOSAGE AND ADMINISTRATION

Ibrutinib is available in capsule (140 mg) and tablet (40 mg, 140 mg, 280 mg, 420 mg, 560 mg) formulations for once-daily oral administration.

Recommended Dosages

Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL) → 420 mg once daily
Mantle Cell Lymphoma (MCL) (relapsed/refractory cases) → 560 mg once daily
Waldenström’s Macroglobulinemia (WM) → 420 mg once daily
Marginal Zone Lymphoma (MZL) → 560 mg once daily
Chronic Graft-versus-Host Disease (cGVHD) → 420 mg once daily

Administration

Ibrutinib should be taken orally once daily at the same time each day. The tablets or capsules must be swallowed whole with a glass of water and should not be crushed, chewed, or broken. It can be taken with or without food, though food may enhance absorption. If a dose is missed, it should be taken as soon as possible on the same day, but double dosing is not recommended.

DRUG INTERACTIONS

CYP3A4 Inhibitors (Increases Ibrutinib levels, risk of toxicity)

Strong: Ketoconazole, Ritonavir, Clarithromycin (Avoid or reduce dose)

Moderate: Fluconazole, Diltiazem, Verapamil (Monitor for toxicity)

CYP3A4 Inducers (Decreases Ibrutinib levels, reduced efficacy)

Rifampin, Carbamazepine, Phenytoin, St. John’s Wort (Avoid use)

Anticoagulants/Antiplatelets (Increases Bleeding risk)

Warfarin, Heparin, Aspirin, Clopidogrel, NSAIDs (Use with caution)

QT-Prolonging Drugs (Increases Arrhythmia risk)

Antiarrhythmics, Antipsychotics, Fluoroquinolones (Monitor ECG)

Immunosuppressants (Increases Infection risk)

Steroids, Other immunosuppressants (Monitor for infections)

CONTRAINDICATIONS

Hypersensitivity to Ibrutinib or any of its components.
Active bleeding disorders or patients on strong anticoagulants (high bleeding risk).
Severe hepatic impairment (metabolism primarily occurs in the liver).
Recent major surgery (risk of impaired wound healing and bleeding).
Pregnancy and breastfeeding (potential fetal harm and drug transfer via milk).

SIDE EFFECTS

Common Side Effects

Diarrhea
Fatigue
Nausea
Muscle and joint pain
Rash
Decreased appetite

Serious Side Effects

Bleeding complications (bruising, nosebleeds, major hemorrhage)
Infections (bacterial, viral, fungal)
Atrial fibrillation (irregular heartbeat, dizziness, shortness of breath)
Hypertension (high blood pressure)
Cytopenias (low blood cell counts: neutropenia, thrombocytopenia, anemia)
Tumor lysis syndrome (TLS) (rapid tumor breakdown causing metabolic imbalances)

TOXICITY

Overdose and Toxic Effects

Symptoms: Severe bleeding, arrhythmias (atrial fibrillation), infections, and organ toxicity.
High doses may increase cytopenias (low blood counts), hypertension, and gastrointestinal toxicity.

Management of Toxicity

Mild to Moderate Toxicity: Supportive care, dose interruption, or reduction.
Severe Toxicity (e.g., major bleeding, life-threatening arrhythmias, TLS): Discontinue Ibrutinib, provide intensive medical management.
No specific antidote: Symptom-based treatment is essential.