Acalabrutinibum

Uses

Acalabrutinibum is a Bruton tyrosine kinase inhibitor used to treat mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma.

Acalabrutinibum is currently indicated for the treatment of adult patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. It has also been recently approved for chronic lymphocytic leukemia and small lymphocytic lymphoma.

Acalabrutinibum is also used to associated treatment for these conditions: Chronic Lymphocytic Leukaemia (CLL), Mantle Cell Lymphoma (MCL), Small Lymphocytic Lymphoma

How Acalabrutinibum works

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.

Acalabrutinibum 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.

Toxicity

Data regarding the toxicity of acalabrutinib is not readily available.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of acalabrutinib. Dose adjustment may be necessary if co-administered.
• Exercise caution with St. John's Wort. The official product labeling recommends avoiding strong CYP3A4 inducers. This herb induces CYP3A metabolism and may reduce serum levels of acalabrutinib.
• Take separate from antacids. Take at least 2 hours before or after antacids.
• Take with a full glass of water.
• Take with or without food.

[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of acalabrutinib.

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

Inhibition of hepatic CYP450 3A4 may also contribute.

The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors.

When acalabrutinib was administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily for 5 days) in healthy subjects, acalabrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3.9- and 5.1-fold, respectively.

Physiologically based pharmacokinetic (PBPK) simulations showed that moderate CYP450 3A4 inhibitors (erythromycin, fluconazole, diltiazem) increased acalabrutinib Cmax and AUC by 2- to nearly 3-fold.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased acalabrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and atrial fibrillation or flutter.

Food may delay the absorption of acalabrutinib, but does not appear to affect the overall extent of absorption.

When a single 75 mg dose of acalabrutinib was administered with a high-fat, high-calorie meal (approximately 918 calories; 59 grams carbohydrate, 59 grams fat, 39 grams protein) in healthy study subjects, mean acalabrutinib Cmax was decreased by 73% and time to reach Cmax was delayed by 1 to 2 hours compared to administration under fasted conditions.

However, mean AUC was not affected.

MANAGEMENT: Acalabrutinibum may be administered with or without food.

Patients should avoid consumption of grapefruit and grapefruit juice during treatment with acalabrutinib.

Acalabrutinibum Drug Interaction

Major: acetaminophen / ibuprofen, aspirin, ticagrelor, apixabanModerate: lactobacillus acidophilus, lactobacillus acidophilus, calcium carbonate, aluminum hydroxide / diphenhydramine / lidocaine / magnesium hydroxide / simethicone topicalUnknown: azithromycin, sulfamethoxazole / trimethoprim, loratadine, pancrelipase, formoterol / mometasone, lidocaine / prilocaine topical, multivitamin, prenatal, alendronate, immune globulin intravenous, metoprolol, ascorbic acid, cholecalciferol

Acalabrutinibum Disease Interaction

Moderate: arrhythmias, bleeding, hepatic impairment, infections, renal impairment

Volume of Distribution

The mean steady-state volume of distribution is approximately 34 L.

Elimination Route

The geometric mean absolute bioavailability of acalabrutinib is 25% with a median time to peak plasma concentrations (Tmax) of 0.75 hours.

Half Life

After administering a single oral dose of 100 mg acalabrutinib, the median terminal elimination half-life of the drug was found to be 0.9 (with a range of 0.6 to 2.8) hours.

The half-life of the active metabolite, ACP-5862, is about 6.9 hours.

Clearance

Acalabrutinibum's mean apparent oral clearance (CL/F) is observed to be 159 L/hr with similar PK between patients and healthy subjects, based on population PK analysis.

Elimination Route

After administration of a single 100 mg radiolabelled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine. An irradiated dose of acalabrutinib was 34.7% recovered as the metabolite ACP-5862; 8.6% was recovered as unchanged acalabrutinub; 10.8 was recovered as a mixture of the M7, M8, M9, M10, and M11 metabolites; 5.9% was the M25 metabolite; 2.5% was recovered as the M3 metabolite.

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