Single-dose pharmacokinetics of ibrutinib in subjects with varying degrees of hepatic impairment^*

Abstract

This open-label, single-dose study was designed to characterize pharmacokinetics and safety profile of ibrutinib in hepatically impaired subjects. Each subject received single oral dose of ibrutinib (140 mg) following an overnight fast (hepatic impairment-mild [n = 6], moderate [n = 10], and severe [n = 8]; healthy control [n = 6]). Subjects with hepatic impairment showed significant increase in ibrutinib plasma exposures and fraction unbound ibrutinib. Compared to control group, mean exposure (AUC_{last; unbound}) in mild, moderate, and severe cohorts was 4.1-, 9.8-, 13.4-fold higher, respectively. Terminal half-life trended slightly longer in moderately and severely impaired subjects, but risk of accumulation on repeated dosing appears negligible as half-life did not exceed 10 h. Based on observed effects on exposure, reduced doses are recommended for patients with mild and moderate liver impairment (Child–Pugh Class A and B), whereas 140 mg is considered too high for severely impaired patients (Class-C). A single dose of 140 mg was well tolerated in this study (NCT01767948).

Keywords:

• Hepatic impairment
• ibrutinib
• pharmacokinetic
• safety

Acknowledgments

Dr. Shalini Nair (SIRO Clinpharm Pvt. Ltd.) provided writing assistance and Dr. Namit Ghildyal (Janssen Research & Development, LLC) provided additional editorial support for this manuscript. Authors thank Deborah Conover, Aline Laenen and Christopher Jones for their contributions to the study and Daniele Ouellet for critically reviewing the manuscript. Authors also thank the study participants, without whom this study would never have been accomplished, and the investigators for their participation in this study.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.1080/10428194.2016.1189548.

Funding information

This study was supported by funding from Janssen Research & Development, LLC.