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.

Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation mediated by glycoprotein VI

“…Indeed, there is retrospective clinical evidence that doses less than 6 mg/kg are as effective as 6 mg/kg for treating CLL 32 and a prospective clinical trial using doses as low as 2.5 mg/kg is being undertaken. 33 …”

A receptor tyrosine kinase ROR1 inhibitor (KAN0439834) induced significant apoptosis of pancreatic cells which was enhanced by erlotinib and ibrutinib

“…Erlotinib, a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR), is the only RTK targeting agent, which has been approved for treatment of advanced pancreatic cancer but with minor clinical effect [ 4 ]. Ibrutinib, a BTK inhibitor, with off-target effects including EGFR [ 6 ] is in phase II-III clinical trials for advanced pancreatic carcinoma ( www.clinicaltrials.gov ).…”

Recent therapeutic advances in chronic lymphocytic leukemia

“…Another approach to minimize the off-target toxicities of ibrutinib while preserving efficacy may be the exploration of lower doses 74 . This is based on the observations that ibrutinib doses of at least 2.5 mg/kg per day were sufficient to achieve at least 95% BTK occupancy in the phase 1 trial in patients with R/R B-cell malignancies 75 and that BTK levels decline over time in CLL cells from ibrutinib-treated patients 76 , 77 .…”

“…Since ibrutinib is an irreversible inhibitor of BTK and binds to BTK in a 1:1 stoichiometric ratio, this would imply the need for lower doses of ibrutinib over time as BTK levels decline. Therefore, continued dosing at 420 mg/day could lead to greater off-target binding and toxicity 74 . Our group is currently studying the pharmacodynamic correlates, including BTK occupancy, of progressively lower dosing of ibrutinib in patients with CLL in the context of a pilot study (NCT02801578).…”