Acalabrutinib
Introduction to Acalabrutinib
Acalabrutinib is a second-generation, highly selective Bruton's tyrosine kinase (BTK) inhibitor used in the treatment of various B-cell malignancies. It was designed to improve upon the first-generation BTK inhibitor ibrutinib, offering enhanced selectivity and potentially fewer off-target effects. Acalabrutinib received FDA approval in 2017 for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, and its indications have since expanded to include chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL).
Mechanism of Action
Acalabrutinib is a small molecule inhibitor that covalently binds to Cysteine 481 in the ATP-binding pocket of BTK, leading to irreversible inhibition of the enzyme. BTK is a critical component of the B-cell receptor (BCR) signaling pathway, which plays a crucial role in B-cell proliferation, survival, and migration. By inhibiting BTK, acalabrutinib disrupts these processes in malignant B-cells, resulting in cell death and reduced tumor growth.
The high selectivity of acalabrutinib for BTK minimizes off-target effects on other kinases, such as EGFR, ITK, and TEC family kinases. This selectivity potentially results in an improved safety profile compared to less selective BTK inhibitors, particularly regarding adverse effects like diarrhea, rash, and atrial fibrillation.
Indications
Acalabrutinib is FDA-approved for the following indications in adult patients:
- Mantle cell lymphoma (MCL) in patients who have received at least one prior therapy
- Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
It is approved as a single agent and in combination with obinutuzumab for CLL/SLL. While these indications are for adult patients, research is ongoing to explore its potential use in pediatric populations with B-cell malignancies.
Off-label uses being investigated include:
- Waldenström's macroglobulinemia
- Diffuse large B-cell lymphoma
- Follicular lymphoma
- Multiple myeloma
Dosage and Administration
The recommended dosage of acalabrutinib for adult patients is:
- 100 mg orally twice daily, approximately 12 hours apart
Acalabrutinib can be taken with or without food. The capsules should be swallowed whole with water and should not be opened, broken, or chewed. If a dose is missed by more than 3 hours, it should be skipped, and the next dose should be taken at its regularly scheduled time.
Dose modifications may be necessary based on adverse reactions or drug interactions. It's important to note that dosing in pediatric patients has not been established and requires further research.
Adverse Effects
Common adverse effects of acalabrutinib include:
- Headache (often transient and resolving within the first month of treatment)
- Diarrhea
- Fatigue
- Myalgia
- Anemia
- Neutropenia
- Upper respiratory tract infection
- Bruising
- Nausea and vomiting
More serious adverse effects, although less common, may include:
- Hemorrhage
- Infections
- Cytopenias
- Second primary malignancies
- Atrial fibrillation and flutter (less common than with ibrutinib)
Compared to ibrutinib, acalabrutinib has shown a lower incidence of certain adverse effects, particularly atrial fibrillation, severe bleeding events, and arthralgia. This improved safety profile is attributed to its higher selectivity for BTK.
Drug Interactions
Acalabrutinib is primarily metabolized by cytochrome P450 3A (CYP3A) enzymes. Significant drug interactions include:
- Strong CYP3A inhibitors: Avoid concomitant use. If a strong CYP3A inhibitor will be used short-term, interrupt acalabrutinib treatment.
- Moderate CYP3A inhibitors: Reduce acalabrutinib dose to 100 mg once daily.
- Strong CYP3A inducers: Avoid concomitant use. If a strong CYP3A inducer cannot be avoided, increase acalabrutinib dose to 200 mg twice daily.
- Gastric acid reducing agents: Acalabrutinib solubility decreases with increasing pH. Separate dosing by at least 2 hours from H2-receptor antagonists and antacids. Consider alternatives to proton-pump inhibitors.
Patients should be monitored for potential drug interactions, especially when starting or stopping medications that affect CYP3A metabolism or gastric pH.
Pediatric Considerations
While acalabrutinib has shown efficacy in adult patients with B-cell malignancies, its use in pediatric populations is still under investigation. Key considerations for pediatricians include:
- Safety and efficacy in children have not been established. Clinical trials are ongoing to evaluate its potential in pediatric B-cell malignancies.
- Dosing regimens for children have not been determined and may differ from adult dosing due to differences in pharmacokinetics and body size.
- Long-term effects on growth and development are unknown and require careful monitoring in any pediatric clinical trials or off-label use.
- The impact on the developing immune system in children needs thorough evaluation, given the role of BTK in normal B-cell development.
- Potential drug interactions with medications commonly used in pediatric populations need to be carefully considered.
- The twice-daily dosing schedule may present adherence challenges in pediatric patients, particularly adolescents.
- Pediatric-specific formulations may be necessary to ensure accurate dosing and ease of administration in younger patients.
Pediatricians should stay informed about ongoing research, including the results of pediatric clinical trials, to guide potential future use of acalabrutinib in pediatric oncology.
