Abstract B20: Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study.
Authors: Skee Donna , Jong Jan De , Hellemans Peter , Swerts Dominique , Conover Deborah , Jones Christopher , Lawitz Eric , Marbury Thomas , Smith William , Chauhan Vijay , Jiao Juhui James , Sukbuntherng Juthamas , Mannaert Erik 
Published: August 2015

Background: Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase, and is extensively metabolized by CYP3A. No subjects with clinically significant hepatic impairment have been enrolled in the clinical efficacy and safety studies performed to date and more data are needed to understand the safety of ibrutinib in this patient population.

Methods: This was an open-label, multi-center, single-dose study in 30 subjects with pharmacokinetic (PK) sampling up to 96 h postdose. Ibrutinib was administered orally at 140 mg following an overnight fast to non-cancer subjects with mild (n=6), moderate (n=10), and severe (n=8) hepatic impairment according to Child-Pugh, and to age- and weight-matched control subjects (n=6).

Results: Subjects with mild, moderate, and severe hepatic impairment, but who were otherwise healthy, showed a significant increase in ibrutinib plasma exposures, as well as fraction unbound ibrutinib, with increasing impairment. Regardless of the severity of hepatic impairment, ibrutinib plasma concentration versus time profiles showed an elimination profile with an initial rapid decline which became gradual towards the terminal phase. Compared to control subjects, mean unbound exposure (AUClast,unbound) in the mild, moderate, and severe cohorts was 4.4-, 9.6-, and 13-fold higher. Compared with normal hepatic function, Cmax of unbound ibrutinib increased 5.7- to 9.9- fold with increasing hepatic impairment. Terminal half-life trended slightly higher in moderately and severely impaired subjects, but the risk for accumulation on repeated dosing appears negligible as half-life did not exceed 10 hours. Urinary excretion of unchanged ibrutinib, although increasing with severity of hepatic impairment, remained negligible at &lt;&lt; 1% of the dose. A single dose of 140 mg was well tolerated in this study.

Conclusion: Based on the observed effect on plasma exposure, the recommended doses for patients with mild and moderate liver impairment are 280 mg/day and 140 mg/day (Child-Pugh Class A and B), respectively. Since no lower capsule strengths are currently available, it is not recommended to administer ibrutinib to patients with severe liver impairment (Child-Pugh Class C).

Citation Format: Donna Skee, Jan De Jong, Peter Hellemans, Dominique Swerts, Deborah Conover, Christopher Jones, Eric Lawitz, Thomas Marbury, William Smith, Vijay Chauhan, Juhui James Jiao, Juthamas Sukbuntherng, Erik Mannaert. Pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment: Results from an open-label, multicenter study. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr B20.