Mechanism of action

It is a selective, oral, second-generation Bruton’s tyrosine kinase (BTK) inhibitor. The mechanism of action of acalabrutinib is the inhibition of BTK, an enzyme involved in the B-cell activation signaling pathway, leading to decreased proliferation and survival of B-cells

Spectrum

The spectrum of activity of acalabrutinib is primarily in hematologic malignancies, such as mantle cell lymphoma and chronic lymphocytic leukemia (CLL). It has also shown efficacy in other B-cell lymphomas

DRUG INTERACTION

Contraindicated  

Serious Use Alternative  

Monitor Closely  

Minor  

Frequency defined:

>10%

All grades

Decreased platelets

Decreased neutrophils

Fatigue

Bruising

Rash

Constipation

Decreased hemoglobin

Headache

Diarrhea

Myalgia

Nausea

Abdominal pain

Grade≥3

Decreased neutrophils

Decreased hemoglobin

Vomiting

Decreased platelets

1-10%

All grades

Neutropenia

Thrombocytopenia

Upper respiratory tract infection

Musculoskeletal pain

Bruising

Diarrhea

Rash

Arthralgia

Nausea

Urinary tract infection

Anemia

Headache

Increased AST

Fatigue

Increased ALT

Increased uric acid

Dizziness

Hemorrhage

Increased bilirubin

Grade ≥3

Increased uric acid

Anemia

Lymphocytosis

Neutropenia

Infection

thrombocytopenia

<1%

All grades

Epistaxis

Hemorrhage

Grade ≥3

Increased AST

Headache

Vomiting

Increased ALT

Diarrhea

Abdominal pain

1-10% (In combination with Obinutuzumab)

Grade ≥3

Diarrhea

Fatigue

Musculoskeletal pain

Arthralgia

Lower respiratory tract infections

upper respiratory tract infections

rash

hemorrhage

headache

<1%(Monotherapy)

Grade ≥3

Fatigue

rash

hemorrhage

nausea

myalgia

Post-marketing reports

Opportunistic infections

 

 

Contraindications

None

Caution

• Hemorrhage: It may increase the risk of bleeding.
• Infection: It can impair the immune system’s ability to fight off infections.
• Atrial Fibrillation: It has been associated with an increased risk of atrial fibrillation.
• Hypertension: It may cause or worsen hypertension.
• Pneumonia: It may increase the risk of pneumonia.
• Tumor Lysis Syndrome: It can cause rapid tumor lysis in some patients with high tumor burden, leading to life-threatening metabolic imbalances.
• Drug Interactions: It may interact with other medications, such as anticoagulants, antiplatelet drugs, and CYP3A inhibitors.

Pregnancy consideration: It may cause foetal harm when administered

Pregnancy category: D

Lactation: Excretion of the drug in human breast milk is unknown

Pregnancy category:

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women.

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.

Category D: adequate data available with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.

Category N: There is no data available for the drug under this category

Pharmacology

It selectively inhibits Bruton’s tyrosine kinase (BTK), a signaling molecule in the B-cell antigen receptor (BCR) and cytokine receptor pathways. Inhibition of BTK results in the suppression of B-cell activation, proliferation, trafficking, chemotaxis, and adhesion.

acalabrutinib and its active metabolite, ACP-5862, form a covalent bond with a cysteine residue in the BTK active site, which leads to long-lasting inhibition of BTK enzymatic activity. This specific mechanism of action makes acalabrutinib a selective and potent BTK inhibitor.

Pharmacodynamics

The pharmacodynamics of acalabrutinib can be described as follows:

• Mode of action: It forms a covalent bond with a cysteine residue in the BTK active site, leading to long-lasting inhibition of BTK activity.
• B-cell inhibition: BTK is a signaling molecule in the B-cell antigen receptor (BCR) and cytokine receptor pathways. Inhibition of BTK results in the suppression of B-cell activation, proliferation, trafficking, chemotaxis, and adhesion.
• Dose-response relationship: The effect of acalabrutinib on BTK activity is dose-dependent, meaning that as the dose increases, the degree of inhibition also increases
• Time-response relationship: The inhibition of BTK activity by acalabrutinib is rapid and sustained, with a half-life of approximately 24 hours
• Drug-drug interactions: It may interact with other medications that are CYP3A inhibitors, leading to increased plasma concentrations of acalabrutinib

Pharmacokinetics

Absorption

• Absolute bioavailability: 25%
• Peak plasma concentration: 563 ng/mL for acalabrutinib and 451 ng/mL for its active metabolite ACP-5862.
• AUC: 1843 ng·hr/mL for acalabrutinib and 3947 ng·hr/mL for ACP-5862.
• Peak plasma time: 0.9 hr for the capsule and 0.5 hr for the tablet (acalabrutinib); 1.6 hr for the capsule and 0.75 hr for the tablet (ACP-5862).
• Effect of food: Administration with a high-fat, high-calorie meal decreased peak plasma concentration by 73% and delayed peak plasma time by 1-2 hours.

Distribution

• Protein bound: 97.5% (acalabrutinib); 98.6% (ACP-5862).
• Vd (steady-state): ~101 L (acalabrutinib); 67 L (ACP-5862)

Metabolism

• Predominantly metabolized by CYP3A enzymes and to a minor extent by glutathione conjugation and amide hydrolysis.
• Active metabolite: ACP-5862, with mean exposure (AUC) ~2- to 3-fold higher than acalabrutinib; ACP-5862 is ~50% less potent than acalabrutinib about BTK inhibition

Elimination/excretion

• Half-life: 1 hour (acalabrutinib); 3.5 hours (ACP-5862).
• Oral clearance: 71 L/hr (acalabrutinib); 13 L/hr (ACP-5862).
• Excretion: 84% feces and 12% urine

Administration

It is administered orally as either a capsule or a tablet. The recommended dose is 100 mg taken orally twice daily until disease progression or unacceptable toxicity occurs. The capsule and tablet are bioequivalent, and food does not affect the bioavailability of acalabrutinib

Patient information leaflet

Generic Name: acalabrutinib

Pronounced: [ a-KAL-a-BROO-ti-nib ]

Why do we use acalabrutinib?

It is a medication used to treat several types of cancer, including:

• Mantle cell lymphoma: It is used in treating mantle cell lymphoma (MCL) in people who have received at least one prior therapy
• Chronic lymphocytic leukemia (CLL): It is used to treat adult patients with CLL, including those with or without 17p deletion
• Waldenström’s macroglobulinemia (WM): It treats adult patients with WM who have received at least one prior therapy