Acalabrutinib

Introduction Overview

Generic Name

acalabrutinib

Brand Name

Calquence

Dosage Form

Oral 100 mg capsule and oral 100 mg film-coated tablet. The capsule and tablet are not identical for gastric acid-reducing drug instructions.

Drug Class

Bruton tyrosine kinase (BTK) inhibitor; targeted therapy for B-cell malignancies.

Pharmacokinetics

Absorption:
Acalabrutinib is taken by mouth, usually every 12 hours. It may be taken with or without food. The capsule formulation depends on gastric acidity for optimal absorption and has special instructions with antacids, H2 blockers, and proton pump inhibitors. The tablet formulation was developed so it can be taken with gastric acid-reducing agents.

Distribution:
Acalabrutinib and its active metabolite circulate bound to plasma proteins and distribute to lymphoid tissues where malignant B cells receive survival signals through the B-cell receptor pathway.

Metabolism:
Acalabrutinib is metabolized mainly by CYP3A. Its major active metabolite, ACP-5862, also inhibits BTK. This makes CYP3A inhibitors and inducers clinically important drug interaction concerns.

Elimination:
The parent drug has a short plasma half-life, but covalent BTK binding supports sustained pharmacodynamic activity. Most drug-related material is eliminated in feces, with a smaller urinary component. Severe hepatic impairment can increase exposure, so use is avoided in that setting.

Dosage Forms

Available dosage forms:
- Calquence capsules: 100 mg.
- Calquence tablets: 100 mg.

Usual adult dose:
100 mg by mouth approximately every 12 hours until disease progression or unacceptable toxicity, unless the label recommends a temporary hold or dose adjustment.

Combination regimens:
- In CLL/SLL, acalabrutinib may be used alone or with obinutuzumab. When used with obinutuzumab, acalabrutinib is typically started first and obinutuzumab is added according to the label regimen.
- In previously untreated mantle cell lymphoma, acalabrutinib may be used with bendamustine and rituximab according to the current labeled regimen, then continued as directed.

Administration:
Swallow capsules or tablets whole with water. Do not open, break, crush, dissolve, or chew. If a dose is missed by more than 3 hours, skip it and take the next dose at the regular time.

Mechanism Of Action

Acalabrutinib inhibits Bruton tyrosine kinase, a key enzyme in B-cell receptor signaling. BTK helps B cells receive signals for activation, proliferation, adhesion, migration, and survival. Many B-cell cancers depend on this pathway.

Acalabrutinib binds covalently to cysteine 481 in the BTK active site, causing sustained BTK inhibition. Blocking BTK weakens survival signaling in malignant B cells, helping control diseases such as chronic lymphocytic leukemia, small lymphocytic lymphoma, and mantle cell lymphoma.

For students, the simple model is: malignant B cells use BTK as part of their "stay alive and grow" wiring. Acalabrutinib turns down that wiring.

Pharmacological Actions

Irreversibly inhibits BTK in the B-cell receptor signaling pathway.
Reduces malignant B-cell activation, proliferation, migration, and survival signaling.
Promotes disease control in CLL, SLL, and MCL.
Can be combined with anti-CD20 antibodies or chemoimmunotherapy in selected labeled regimens.
Has fewer off-target kinase effects than first-generation BTK inhibition, though serious toxicities still occur.
Maintains activity through covalent target binding despite a short parent-drug half-life.

Therapeutic Or Clinical Uses

Chronic lymphocytic leukemia in adults.
Small lymphocytic lymphoma in adults.
Mantle cell lymphoma in adults who have received at least one prior therapy.
Previously untreated mantle cell lymphoma in adults when used in the labeled combination regimen with bendamustine and rituximab.
May be used as continuous oral targeted therapy until progression or unacceptable toxicity.

Side Or Adverse Effects

Headache, diarrhea, nausea, abdominal discomfort, fatigue, musculoskeletal pain, and rash.
Upper respiratory tract infection, pneumonia, urinary tract infection, and opportunistic infections.
Bleeding events, including bruising, petechiae, nosebleeds, gastrointestinal bleeding, and rare major or fatal hemorrhage.
Cytopenias, including neutropenia, anemia, thrombocytopenia, and lymphopenia.
Atrial fibrillation, atrial flutter, and other cardiac arrhythmias, including rare serious ventricular arrhythmias.
Second primary malignancies, especially skin cancers.
Hepatotoxicity, including liver enzyme elevations and clinically significant liver injury.
Dizziness, cough, vomiting, and decreased appetite may occur.

Precautions

Monitor complete blood counts regularly and manage severe cytopenias with interruption, dose modification, or supportive care.
Monitor for infection and consider prophylaxis in patients at increased risk for opportunistic infection.
Assess bleeding risk, especially in patients taking anticoagulants, antiplatelet drugs, NSAIDs, or supplements that affect bleeding.
Consider holding acalabrutinib before and after surgery or invasive procedures based on bleeding risk.
Monitor for new palpitations, dizziness, syncope, shortness of breath, chest discomfort, or irregular heartbeat.
Use sun protection and monitor for skin cancers.
Monitor liver tests as clinically indicated and evaluate symptoms of liver injury.
Avoid use in severe hepatic impairment.
Use effective contraception during treatment and for at least 1 week after the last dose because fetal harm may occur.
Do not breastfeed during treatment and for at least 2 weeks after the final dose.

Warnings

Serious and opportunistic infections can occur and may be fatal.
Major hemorrhage can occur, with increased risk when combined with antithrombotic medicines.
Cytopenias can be severe and require monitoring.
Second primary malignancies, including skin cancer, have been reported.
Cardiac arrhythmias, including atrial fibrillation/flutter and serious ventricular arrhythmias, have occurred.
Hepatotoxicity, including severe and potentially life-threatening liver injury, has been reported.
Embryo-fetal toxicity can occur based on mechanism and animal data.

Contraindication

Current U.S. prescribing information lists no formal contraindications for Calquence. Severe hepatic impairment, pregnancy risk, breastfeeding avoidance, active serious infection, major bleeding risk, and interacting drugs are handled as warnings, precautions, dose-modification issues, or not-recommended uses rather than label-listed absolute contraindications.

Drug Interactions

Strong CYP3A inhibitors can increase acalabrutinib exposure; avoid or temporarily interrupt therapy according to label guidance.
Moderate CYP3A inhibitors can increase exposure; dose reduction is recommended while the inhibitor is used.
Strong CYP3A inducers can lower exposure and reduce effectiveness; avoid when possible.
Antithrombotic medicines, including anticoagulants and antiplatelet drugs, can increase bleeding risk.
For capsules: separate antacids by at least 2 hours, take the capsule 2 hours before an H2 blocker, and avoid proton pump inhibitors.
For tablets: gastric acid-reducing agents, including proton pump inhibitors, H2 blockers, and antacids, may be used without the capsule-specific restrictions.
Avoid St. John's wort because it can induce CYP3A and reduce acalabrutinib exposure.

Preparations Of The Drug

Calquence 100 mg capsules.
Calquence 100 mg film-coated tablets.
Capsules and tablets should be swallowed whole and not crushed, opened, dissolved, or chewed.
Store according to product labeling at controlled room temperature.
Dispense in original packaging or pharmacy-approved packaging that protects the product and supports correct twice-daily use.

Student Key Points

Acalabrutinib is a BTK inhibitor for B-cell cancers.
The usual dose is 100 mg twice daily.
Capsules and tablets differ for acid-reducing drug instructions.
Major safety themes are infection, bleeding, cytopenias, arrhythmias, skin cancer, and liver injury.
Current label contraindications are none, but that does not remove the need for careful monitoring.