Brutinacib-100

Indications

• Chronic lymphocytic leukemia (CLL)
• Mantle cell lymphoma (MCL)
• Other B-cell malignancies as determined by specialist oncologists

Dosage

Adults: The recommended dose of Acalabrutinib is 100 mg taken orally twice daily. In cases of severe interactions with CYP3A4 inhibitors, a dose reduction to 100 mg once daily may be necessary. Regular monitoring of blood counts and liver enzymes is advised during treatment.

Mechanism of action

Acalabrutinib selectively and irreversibly inhibits Bruton's tyrosine kinase (BTK), a critical component of the B-cell receptor signaling pathway. This inhibition leads to decreased activation of downstream signaling cascades that promote B-cell survival and proliferation, thereby inducing apoptosis in malignant B cells.

Pharmacodynamics

The pharmacodynamics of Acalabrutinib involve the selective blockade of BTK, which is vital for B-cell receptor signaling. This blockade results in a reduction of B-cell activation, migration, and proliferation. The drug's efficacy is particularly notable in B-cell malignancies, where BTK plays a pivotal role in the pathogenesis and maintenance of the disease.

Pharmacokinetics

Acalabrutinib is rapidly absorbed, with peak plasma concentrations reached within 1-3 hours post-administration. The drug has an oral bioavailability of approximately 100%. It is primarily metabolized by the liver via CYP3A4, and its elimination half-life is approximately 2-3 hours. Acalabrutinib's clearance is impacted by concomitant use of CYP3A4 inhibitors or inducers, necessitating dosage adjustments in such cases.

Adverse effects

• alopecia
• anaemia
• appetite decreased
• decreased leucocytes
• diarrhoea
• dizziness
• dyspepsia
• embolism
• thrombosis
• excessive tearing

Interactions

• antifungals, azoles (severe, increases exposure)
• cobicistat (severe, increases exposure)
• idelalisib (severe, increases exposure)
• mitotane (severe, decreases exposure)
• St. John's Wort (severe, decreases exposure)
• clarithromycin (severe, increases exposure)
• rifampicin (severe, decreases exposure)
• crizotinib (unknown, increases exposure)
• dabrafenib (unknown, decreases exposure)
• imatinib (unknown, increases exposure)

Precautions

• Monitor full blood count and liver enzymes before starting treatment and periodically during therapy.
• Caution in patients with severe renal impairment, monitor for signs of toxicity.
• Patients should be advised to seek medical advice at the first sign of loose stools.
• Patients should be cautioned about potential side effects affecting driving and skilled tasks due to fatigue and dizziness.

Pregnancy

Acalabrutinib is not recommended during pregnancy due to potential harm to the fetus. Women of childbearing potential should use effective contraception during treatment and for a period after discontinuation.

Breast-feeding

There are no data on the excretion of acalabrutinib in human milk. Due to potential serious adverse reactions in breastfed infants, breastfeeding is not recommended during treatment.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Capsule: 100 mg

Mechanism of action

Mantle Cell Lymphoma (MCL) is a rare yet aggressive type of B-cell non-Hodgkin lymphoma (NHL) with poor prognosis. Subsequently, relapse is common in MCL patients and ultimately represents disease progression. Lymphoma occurs when immune system lymphocytes grow and multiply uncontrollably. Such cancerous lymphocytes may travel to many parts of the body, including the lymph nodes, spleen, bone marrow, blood, and other organs where they can multiply and form a mass(es) called a tumor. One of the main kinds of lymphocytes that can develop into cancerous lymphomas are the body's own B-lymphocytes (B-cells). Bruton Tyrosine Kinase (BTK) is a signalling molecule of the B-cell antigen receptor and cytokine receptor pathways. Such BTK signaling causes the activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Acalabrutinib is a small molecule inhibitor of BTK. Both acalabrutinib and its active metabolite, ACP-5862, act to form a covalent bond with a cysteine residue (Cys481) in the BTK active site, leading to inhibition of BTK enzymatic activity. As a result, acalabrutinib inhibits BTK-mediated activation of downstream signaling proteins CD86 and CD69, which ultimately inhibits malignant B-cell proliferation and survival Whereas ibrutinib is typically recognized as the first-in-class BTK inhibitor, acalabrutinib is considered a second generation BTK inhibitor primarily because it demonstrates highter selectivity and inhibition of the targeted activity of BTK while having a much greater IC50 or otherwise virtually no inhibition on the kinase activities of ITK, EGFR, ERBB2, ERBB4, JAK3, BLK, FGR, FYN, HCK, LCK, LYN, SRC, and YES1. In effect, acalabrutinib was rationally designed to be more potent and selective than ibrutinib, all the while demonstrating fewer adverse effects - in theory - because of the drug's minimized off target effects.

Pharmacodynamics

Acalabrutinib is a Bruton Tyrosine Kinase inhibitor that prevents the proliferation, trafficking, chemotaxis, and adhesion of B cells. It is taken every 12 hours and can cause other effects such as atrial fibrillation, other malignancies, cytopenia, hemorrhage, and infection.