Ibrutinib

Ibrutinib Uses, Dosage, Side Effects, Food Interaction and all others data.

Ibrutinib is a small-molecule inhibitor of BTK. Ibrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK enzymatic activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. BTK’s role in signaling through the B-cell surface receptors results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Nonclinical studies show that ibrutinib inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.

In vitro studies have shown an induction of CLL cell apoptosis even in presence of prosurvival factors. It has also been reported an inhibition of CLL cell survival and proliferation as well as an impaired in cell migration and a reduction in the secretion of chemokines such as CCL3 and CCL4. The latter effect has been shown to produce regression in xenograft mouse models.

Clinical studies for relapsed/refractory CLL in phase I and II showed an approximate 71% of overall response rate.. In the case of relapsed/refractory mantle cell lymphoma, approximately 70% of the tested patients presented a partial or complete response.. In clinical trials for relapsed/refractory diffuse large B-cell lymphoma, a partial response was found in between 15-20% of the patients studied; while for patients with relapsed/refractory Waldenstrom's macroglobulinemia, a partial response was observed in over 75% of the patients tested. Finally, for patients with relapsed/refractory follicular lymphoma, a partial to complete response was obtained in approximately 54% of the patients.

Trade Name Ibrutinib
Availability Prescription only
Generic Ibrutinib
Ibrutinib Other Names Ibrutinib
Related Drugs Imbruvica, Venclexta, prednisone, methotrexate, dexamethasone, mycophenolate mofetil, rituximab, Rituxan, cyclophosphamide, Revlimid
Weight 140mg, 70mg, 140mg, 280mg, 420mg, 560mg
Type Oral capsule, oral tablet
Formula C25H24N6O2
Weight Average: 440.507
Monoisotopic: 440.196074037
Protein binding

Irreversible plasma protein binding increases gradually over time and reaches 25% of the administered dose 8 hours after initial administration. From the plasma proteins, ibrutinib has been shown to be mainly bound to albumin and to bind to α1 AGP. The irreversible protein binding of ibrutinib to plasma proteins can account for 97.3% of the administered dose.

Groups Approved
Therapeutic Class Targeted Cancer Therapy
Manufacturer
Available Country United States
Last Updated: September 19, 2023 at 7:00 am
Ibrutinib
Ibrutinib

Uses

Ibrutinib, is a kinase inhibitor used for the treatment of patients with:

  • Mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
  • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
  • Chronic lymphocytic leukemia with 17p deletion
  • Waldenström's macroglobulinemia (WM)

Ibrutinib is also used to associated treatment for these conditions: Chronic Lymphocytic Leukaemia (CLL), Mantle Cell Lymphoma (MCL), Waldenström's Macroglobulinemia (WM)

How Ibrutinib works

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.

Dosage

Ibrutinib dosage

Mantle cell lymphoma: 560 mg taken orally once daily (four 140 mg capsules once daily)

Chronic lymphocytic leukemia and Waldenström's macroglobulinemia: 420 mg taken orally once daily (three 140 mg capsules once daily)

Capsules should be taken orally with a glass of water. The capsules should not be opened, broke, or chewed

Side Effects

The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash.

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.

Precaution

Hemorrhage: Should be monitored for bleeding

Infections: Patients should be monitored for fever and infections and evaluated

Cytopenias: Complete blood counts should be checked monthly

Atrial Fibrillation: Patients should be monitored for atrial fibrillation

Second Primary Malignancies: Other malignancies have occurred in patients, including skin cancers, and other carcinomas

Tumor Lysis Syndrome (TLS): Patients should be monitored at risk for TLS (e.g. high tumor burden)

Embryo-Fetal Toxicity: Can cause fetal harm. Women should be advised of the potential risk to a fetus and to avoid pregnancy while taking the drug

Interaction

CYP3A Inhibitors: Co-administration with strong and moderate CYP3A inhibitors should be avoided. If a moderate CYP3A inhibitor must be used, Ibrutinib dose should be reduced

CYP3A Inducers: Co-administration with strong CYP3A inducers should be avoided

Food Interaction

  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of ibrutinib.
  • Avoid St. John's Wort. This herb induces CYP3A4 and may reduce the serum concentration of ibrutinib.
  • Take at the same time every day.
  • Take with a full glass of water.

[Major] GENERALLY AVOID: Coadministration with grapefruit, grapefruit juice, or Seville oranges may significantly increase the plasma concentrations of ibrutinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Pharmacokinetic modeling suggests that other moderate CYP450 3A4 inhibitors such as diltiazem and erythromycin may increase ibrutinib systemic exposure (AUC) by 6- to 9-fold under fasting condition.

The safety and efficacy of these exposures are unknown.

The highest ibrutinib dose evaluated in clinical trials was 12.5 mg br> ADJUST DOSING INTERVAL: Food increases the oral bioavailability of ibrutinib.

The mechanism of interaction is unknown.

According to the product labeling, administration with food increases ibrutinib exposure approximately 2-fold compared to administration after overnight fasting.

MANAGEMENT: Patients treated with ibrutinib should avoid consumption of Seville oranges, grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

Ibrutinib should be taken once daily at approximately the same time each day.

Ibrutinib Hypertension interaction

[Moderate] The use of ibrutinib may cause hypertension.

It is recommended to monitor for new onset hypertension or hypertension that is not adequately controlled after starting therapy and to adjust hypertensive medications and

Close monitoring of blood pressure is recommended.

Volume of Distribution

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

Elimination Route

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.

Half Life

The elimination half-life of ibrutinib is of approximately 4-6 hours.

Clearance

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

Elimination Route

The cumulative excretion of ibrutinib in urine is of about 7.8% of the administered dose and most of this excretion is found during the first 24 hours after administration. In feces, the cumulative excretion accounts for 80% of the administered dose and the excretion occurs within 48 hours of the initial administration. The total excretion of ibrutinib during the first 168 hours after initial administration accounts for 88.5% of the administered dose.

Pregnancy & Breastfeeding use

Pregnancy Category D. Based on animal data, Ibrutinib can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

It is not known whether Ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ibrutinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Special Warning

Pediatric Use: The safety and effectiveness of Ibrutinib in pediatric patients have not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia, urinary tract infection and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Innovators Monograph

You find simplified version here Ibrutinib

Ibrutinib contains Ibrutinib see full prescribing information from innovator Ibrutinib Monograph, Ibrutinib MSDS, Ibrutinib FDA label

*** Taking medicines without doctor's advice can cause long-term problems.
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