Pharmacokinetic and pharmacodynamic evaluation of ibrutinib for the treatment of chronic lymphocytic leukemia: rationale for lower doses

ABSTRACT

Introduction: Ibrutinib, a first-in-class covalent inhibitor of Bruton’s tyrosine kinase (BTK), is approved in many countries for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) and for previously untreated disease with a 17p deletion and, most recently, as a frontline therapy for CLL. In controlled trials in CLL, ibrutinib produced high response rates and improved survival in both the frontline and relapsed settings. While ibrutinib controls CLL with impressive efficacy, it only infrequently induces complete remissions, particularly of relapsed CLL, and does not eradicate minimal residual disease. Finally, ibrutinib is extremely expensive, has off-target toxicities, and requires indefinite therapy.

Areas covered: In this article, we provide an overview of the CLL therapeutic landscape and discuss the pharmacokinetic and pharmacodynamic aspects of ibrutinib. Major clinical trials of ibrutinib in CLL are summarized, and its safety profile explored.

Expert opinion: Ibrutinib represents a transformative advance in CLL management and has validated BTK as a therapeutic target in this disease, but has some limitations, leading to the emergence of other BTK inhibitors and mechanism-based combination strategies. Given complete BTK occupancy at lower doses of ibrutinib and declining levels of BTK on ibrutinib therapy, lower doses of ibrutinib in CLL are being explored.

KEYWORDS:

• Bruton tyrosine kinase
• B-cell receptor
• chronic lymphocytic leukemia
• dosing
• ibrutinib
• pharmacokinetic
• pharmacodynamics

Declaration of interest

VV Gandhi has received research support from Pharmacyclics LLC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute (P30 CA016672).