Usage
Acalabrutinib is prescribed for the treatment of certain types of blood cancers in adults. These include:
- Mantle cell lymphoma (MCL): Prescribed for adult patients who have received at least one prior therapy.
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
Pharmacological Classification: Kinase inhibitor, specifically a Bruton tyrosine kinase (BTK) inhibitor.
Mechanism of Action: Acalabrutinib irreversibly binds to BTK, a key enzyme in B-cell receptor signaling pathways. Inhibiting BTK disrupts the proliferation and survival of malignant B cells, which are involved in these types of cancer.
Alternate Names
Acalabrutinib is the generic name. Brand names include Calquence.
How It Works
Pharmacodynamics: Acalabrutinib primarily targets malignant B cells by irreversibly inhibiting BTK, thereby disrupting downstream signaling crucial for B-cell survival and proliferation. This leads to reduced growth and eventual apoptosis of cancerous B cells.
Pharmacokinetics:
- Absorption: Acalabrutinib is well-absorbed orally, with or without food. However, acidic beverages (like grapefruit or orange juice) can decrease the absorption of the capsule formulation. Tablet formulation does not have this food interaction.
- Metabolism: Primarily metabolized in the liver, mainly by CYP3A4. A major active metabolite, ACP-5862, also contributes to the drug’s activity.
- Elimination: Excreted primarily through feces, with a smaller portion excreted in urine.
Mode of Action: Acalabrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to irreversible inhibition of its kinase activity. This blocks B-cell receptor signaling, inhibiting B-cell activation, proliferation, and survival, ultimately promoting apoptosis of malignant B cells.
Receptor Binding/Enzyme Inhibition: Irreversible covalent inhibition of Bruton tyrosine kinase (BTK).
Elimination Pathways: Primarily hepatic metabolism via CYP3A4, followed by fecal excretion; minor renal excretion.
Dosage
Standard Dosage
Children: The safety and efficacy of acalabrutinib in children have not been established.
Special Cases:
- Elderly Patients: No dose adjustment is required based solely on age. However, close monitoring is advised, as elderly patients may be more susceptible to adverse effects.
- Patients with Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. Limited data are available for patients with severe renal impairment; administer with caution and monitor closely for toxicity.
- Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild or moderate hepatic impairment. However, acalabrutinib should be avoided in patients with severe hepatic impairment.
- Patients with Comorbid Conditions: Close monitoring is recommended for patients with pre-existing cardiovascular disease, history of infections, or bleeding disorders.
Clinical Use Cases
Acalabrutinib’s use is primarily focused on treating CLL, SLL, and MCL. Dosages in these settings follow the standard adult recommendations. There are no specific dosage recommendations for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose adjustments are primarily based on adverse reactions, not specific clinical situations. See the section on “Side Effects” for information on dose modifications based on toxicity.
Side Effects
Common Side Effects:
Headache, diarrhea, fatigue, muscle pain, bruising, bleeding (e.g., nosebleeds, bleeding gums), infections (e.g., upper respiratory tract infections, pneumonia).
Rare but Serious Side Effects:
Severe bleeding events (including intracranial hemorrhage and gastrointestinal bleeding), serious infections (including opportunistic infections), second primary malignancies (including skin cancer), atrial fibrillation and flutter, cytopenias (low blood cell counts).
Long-Term Effects:
The potential long-term effects of acalabrutinib are still being studied. Second primary malignancies and chronic cytopenias are potential concerns.
Adverse Drug Reactions (ADR):
Serious bleeding events, severe infections, atrial fibrillation and flutter, and second primary malignancies are ADRs requiring urgent medical attention.
Contraindications
Known hypersensitivity to acalabrutinib or any component of the formulation.
Drug Interactions
Acalabrutinib is metabolized by CYP3A4 and can interact with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir) and inducers (e.g., rifampin, phenytoin, St. John’s wort). Concomitant use of strong CYP3A4 inhibitors should generally be avoided, or the acalabrutinib dose may need to be reduced. Strong CYP3A4 inducers may necessitate an increased dose of acalabrutinib. Acalabrutinib capsules also have reduced absorption when taken with acidic beverages or antacids/acid reducing agents.
Acalabrutinib may also interact with:
- Anticoagulants/Antiplatelets: Increased risk of bleeding.
- Grapefruit juice: Increased acalabrutinib levels and risk of side effects.
- Other medications metabolized by CYP3A4: Potential for altered drug levels of either acalabrutinib or the interacting drug.
Pregnancy and Breastfeeding
Acalabrutinib may cause fetal harm and dystocia based on animal studies. There are no adequate data in pregnant women. Acalabrutinib should not be used during pregnancy unless the potential benefit outweighs the potential risk to the fetus. Effective contraception should be used during treatment and for at least 1 week after the final dose.
It is unknown whether acalabrutinib is excreted in human milk. Breastfeeding is not recommended during treatment and for 2 weeks after the last dose.
Drug Profile Summary
- Mechanism of Action: Irreversible BTK inhibitor.
- Side Effects: Common: Headache, diarrhea, fatigue, bruising, bleeding, infections. Serious: Severe bleeding, serious infections, second primary malignancies, atrial fibrillation.
- Contraindications: Hypersensitivity.
- Drug Interactions: CYP3A4 inhibitors and inducers, anticoagulants/antiplatelets, grapefruit juice.
- Pregnancy & Breastfeeding: Avoid use during pregnancy unless benefits outweigh risks. Not recommended during breastfeeding.
- Dosage: 100 mg twice daily (every 12 hours).
- Monitoring Parameters: Complete blood counts, liver function tests, signs of bleeding, cardiac rhythm monitoring, skin examinations.
Popular Combinations
Acalabrutinib can be used in combination with obinutuzumab for the treatment of previously untreated CLL.
Precautions
- General Precautions: Monitor for infections, bleeding, cardiac arrhythmias, second primary malignancies. Evaluate hepatic and renal function.
- Pregnant Women: Avoid use. If use is necessary, counsel patient about potential risks.
- Breastfeeding Mothers: Not recommended.
- Children & Elderly: No pediatric data available. Monitor elderly patients closely for adverse effects.
- Lifestyle Considerations: Caution patients regarding sun exposure (increased risk of skin cancer) and potential for bleeding/bruising. Advise against driving or operating machinery if experiencing fatigue or dizziness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Acalabrutinib?
A: The standard recommended dose is 100 mg orally twice daily (approximately every 12 hours) for adults.
Q2: What are the most common side effects of Acalabrutinib?
A: Common side effects include headache, diarrhea, fatigue, muscle pain, bruising, bleeding, and infections.
Q3: What are the serious side effects to watch out for with Acalabrutinib?
A: Serious side effects include major bleeding events, serious infections, second primary malignancies (especially skin cancers), and atrial fibrillation/flutter.
Q4: Can Acalabrutinib be used in patients with liver problems?
A: Acalabrutinib should be avoided in patients with severe hepatic impairment. No dose adjustment is needed for mild or moderate impairment.
Q5: Can Acalabrutinib be used in patients with kidney problems?
A: Acalabrutinib can be used with caution in patients with mild to moderate renal impairment. Limited data are available for severe renal impairment, so careful monitoring is necessary in these patients.
Q6: What are the major drug interactions with Acalabrutinib?
A: Acalabrutinib interacts with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) and inducers (e.g., rifampin). Concomitant use should be avoided or dose adjustments may be needed. It can also interact with anticoagulants and antiplatelets, increasing the risk of bleeding. Grapefruit juice should also be avoided. The capsule form is affected by acidic foods and acid reducing agents.
Q7: Can Acalabrutinib be used during pregnancy or breastfeeding?
A: Acalabrutinib is generally not recommended during pregnancy due to potential risks to the fetus. It’s also not recommended during breastfeeding, as it is not known whether it passes into breast milk.
Q8: What should patients be monitored for while taking Acalabrutinib?
A: Patients should be monitored for signs of infection, bleeding, cardiac arrhythmias (especially atrial fibrillation), and the development of new skin lesions. Regular complete blood counts and liver function tests should also be performed.
Q9: How should patients take Acalabrutinib tablets?
A: Tablets should be swallowed whole with water, with or without food. They should not be chewed, crushed, or split.
Q10: How should patients take Acalabrutinib capsules?
A: Capsules should be swallowed whole with water, with or without food. Do not open, break, or chew the capsules. Avoid taking the capsule with acidic foods or drinks (e.g., orange juice, grapefruit juice) or concomitant acid reducing medications as this can affect absorption.
