IBRUTIX CAPSULES

Indications

• Chronic lymphocytic leukaemia (CLL)
• Mantle cell lymphoma (MCL)
• Other B-cell malignancies

Dosage

Children: Refer to BNF for Children for specific paediatric dosing information.

Adults: The usual dose of Ibrutinib for adults is 420 mg taken orally once daily. Dose adjustments may be required based on hepatic function and potential drug interactions.

Mechanism of action

Ibrutinib irreversibly inhibits BTK by forming a covalent bond with a cysteine residue in the active site (Cys481). This inhibition prevents phosphorylation of downstream substrates involved in B-cell receptor signaling, thus impairing the survival and proliferation of B-cell malignancies and promoting apoptosis in these cells.

Pharmacodynamics

Clinical studies have demonstrated that Ibrutinib induces apoptosis in CLL cells, even in the presence of prosurvival factors. It inhibits CLL cell survival and proliferation, impairs cell migration, and reduces chemokine secretion, contributing to therapeutic efficacy. The drug has shown an overall response rate of approximately 71% in relapsed/refractory CLL and around 70% in relapsed MCL, with significant responses also observed in other B-cell malignancies.

Pharmacokinetics

Ibrutinib is well absorbed following oral administration, with peak plasma concentrations occurring within 1-2 hours. The drug has a half-life of about 4-6 hours. It is primarily metabolized by the liver via the cytochrome P450 system, particularly CYP3A4. The renal clearance of Ibrutinib is low, and it is excreted mainly in feces. Dose adjustments may be necessary in patients with hepatic impairment.

Adverse effects

• stomatitis
• thrombocytopenia
• tumour lysis syndrome
• blurred vision
• vomiting
• angioedema
• hepatitis B reactivation
• leukostasis syndrome
• panniculitis
• anaemia
• hepatic failure
• progressive multifocal leukoencephalopathy (PML)
• Stevens-Johnson syndrome
• ventricular tachyarrhythmia

Interactions

• grapefruit juice + ibrutinib: Severe (increases exposure)
• St. John's Wort + ibrutinib: Severe (decreases exposure)
• belzutifan + ibrutinib: Moderate (decreases exposure)
• cenobamate + ibrutinib: Moderate (decreases exposure)
• tucatinib + ibrutinib: Moderate (increases exposure)
• ibrutinib + aliskiren: Unknown (increases exposure)
• amiodarone + ibrutinib: Unknown (increases exposure)
• dronedarone + ibrutinib: Unknown (increases exposure)
• antifungals, azoles + ibrutinib: Unknown (increases exposure)
• ibrutinib + fexofenadine: Unknown (increases exposure)

Precautions

• Monitor for atrial fibrillation, especially in patients with cardiac risk factors or acute infections
• Perform complete ECG if arrhythmic symptoms or dyspnoea develop
• In cases of hepatitis B virus serology, consult a liver disease expert before treatment
• Maintain adequate hydration in renal impairment, reduce dose to 280 mg once daily for severe impairment

Pregnancy

Manufacturer advises to avoid due to toxicity in animal studies.

Breast-feeding

Manufacturer advises caution, as it is unknown if ibrutinib is excreted in human milk.

Storage

Store at room temperature (15-30 degrees Celsius) in a tightly closed container, away from moisture and heat.

Formulations

• Tablet

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. Ibrutinib is a novel oral tyrosine kinase inhibitor that irreversibly binds and inhibits tyrosine-protein kinase BTK (Bruton tyrosine kinase). BTK has been found to be important in the function of B-cell receptor signaling and therefore in the maintenance and expansion of various B-cell malignancies including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Targeting BTK with ibrutinib has been found to be an effective strategy in treating these malignancies. Phase I clinical testing in non-Hodgkin's lymphomas and CLL showed that the drug was extremely well tolerated with no major dose-limiting toxicities and a 54% overall response rate. Subsequently, two phase Ib/II studies were performed on patients with CLL, one in relapsed/refractory CLL and one in previously untreated elderly patients with CLL. Both of these studies continued to show good tolerability of the drug and an overall response rate of about 71% with extended duration of response. Another phase II study using ibrutinib in relapsed/refractory MCL was conducted and also showed that it was well tolerated with an overall response rate of 68% and extended duration of response. Due to these results, the U.S. Food and Drug Administration granted accelerated approval for ibrutinib in November 2013 for patients with MCL who had received at least one prior therapy and in February 2014 for patients with CLL who had received at least one prior therapy. This review will discuss the preclinical pharmacology, pharmacokinetics and clinical efficacy to date of ibrutinib in the treatment of CLL and MCL. ... In this study we report for the first time that ibrutinib is cytotoxic to malignant plasma cells from patients with multiple myeloma (MM) and furthermore that treatment with ibrutinib significantly augments the cytotoxic activity of bortezomib and lenalidomide chemotherapies. We describe that the cytotoxicity of ibrutinib in MM is mediated via an inhibitory effect on the nuclear factor-(k)B (NF-(k)B) pathway. Specifically, ibrutinib blocks the phosphorylation of serine-536 of the p65 subunit of NF-(k)B, preventing its nuclear translocation, resulting in down-regulation of anti-apoptotic proteins Bcl-xL, FLIP(L) and survivin and culminating in caspase-mediated apoptosis within the malignant plasma cells.... Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that characteristically shows overexpression of cyclin-D1 due to an alteration in the t(11;14)(q13;q32) chromosomal region. Although there are some promising treatment modalities, great majority of patients with this disease remain incurable. The B-cell antigen receptor (BCR) signaling plays a crucial role in B-cell biology and lymphomagenesis. Bruton tyrosine kinase (BTK) has been identified as a key component of the BCR signaling pathway. Evidence suggests that the blockade of BTK activity by potent pharmacologic inhibitors attenuates BCR signaling and induces cell death. Notably, the expression levels and the role of BTK in MCL survival are still elusive. Here, we demonstrated a moderate to strong BTK expression in all MCL cases (n=19) compared to benign lymphoid tissues. Treatment of MCL cell lines (Mino or Jeko-1) with a potent BTK pharmacologic inhibitor, Ibrutinib, decreased phospho-BTK-Tyr(223) expression. Consistent with this observation, Ibrutinib inhibited the viability of both Mino and JeKo-1 cells in concentration- and time-dependent manners. Ibrutinib also induced a concentration-dependent apoptosis in both cell lines. Consistently, Ibrutinib treatment decreased the levels of anti-apoptotic Bcl-2, Bcl-xL, and Mcl-1 protein. These findings sugge

Pharmacodynamics

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.