Acalabrutinib is a Bruton tyrosine kinase inhibitor, commonly abbreviated BTK inhibitor. BTK is a signaling protein involved in B-cell receptor signaling.
Simple explanation
B cells use signaling pathways to receive instructions that influence their growth, activation, movement and survival. Malignant B cells can exploit these pathways.
Acalabrutinib binds to BTK and inhibits its signaling activity. This interferes with processes that support malignant B-cell survival and proliferation.
Detailed mechanism
BTK participates downstream of the B-cell receptor. Its signaling contributes to:
- B-cell activation
- proliferation
- migration
- chemotaxis
- adhesion
- survival
The FDA prescribing information describes acalabrutinib as an inhibitor of BTK and reports inhibition of BTK-mediated downstream signaling in nonclinical studies.
Why BTK matters in CLL and MCL
CLL and MCL are B-cell malignancies. Their malignant cells depend to varying degrees on signaling pathways that regulate B-cell behavior.
By inhibiting BTK, acalabrutinib can reduce signaling required for malignant B-cell activity. This pharmacologic effect is one reason acalabrutinib is used in selected patients with CLL/SLL and MCL.
Pharmacodynamic effect
At the recommended 100 mg twice-daily regimen, FDA labeling reports median steady-state BTK occupancy of at least 95% in peripheral blood maintained over the 12-hour dosing interval in patients with B-cell malignancies.
Targeted therapy does not mean risk-free
BTK signaling has physiological roles, and acalabrutinib’s pharmacologic effects can contribute to adverse reactions. Important risks include bleeding, infections, cytopenias, arrhythmias and liver toxicity.