Ibrutinib is a covalent BTK inhibitor developed as a targeted treatment for B-cell malignancies. Its pharmacology is based on inhibition of BTK signaling.
Pharmacodynamics
BTK participates in B-cell receptor signaling and influences B-cell trafficking, chemotaxis and adhesion. Ibrutinib forms a covalent bond with BTK, producing sustained inhibition of enzymatic activity.
Absorption
Current U.S. pharmacokinetic information reports a median time to peak plasma concentration of approximately 1 to 2 hours.
Protein binding
Ibrutinib is highly protein bound, with reversible binding of approximately 97.3% in vitro.
Distribution
The reported apparent volume of distribution is large, consistent with extensive distribution beyond the plasma compartment.
Metabolism
Metabolism is a major route of elimination. Ibrutinib is metabolized primarily by CYP3A and to a lesser extent by CYP2D6. Its active metabolite, PCI-45227, has lower BTK inhibitory activity than the parent drug.
Half-life
The terminal half-life of ibrutinib is approximately 4 to 6 hours.
Food effect
A high-fat, high-calorie meal increases ibrutinib exposure compared with administration after an overnight fast. This pharmacokinetic characteristic is relevant to consistent administration.
Clinical evidence
Early clinical studies demonstrated substantial activity in relapsed CLL and other B-cell malignancies. In a pivotal relapsed CLL study, ibrutinib produced durable responses and improved progression-related outcomes.
The RESONATE study showed improved progression-free and overall survival compared with ofatumumab in previously treated CLL/SLL.
RESONATE-2 subsequently demonstrated superiority of ibrutinib over chlorambucil in previously untreated older patients with CLL/SLL.
Limitations of clinical evidence
Clinical-trial outcomes describe populations studied under specific protocols. They should not be interpreted as a guarantee of response for an individual patient.