Eribulin mesylate pharmacokinetics in patients with hepatic impairment.

Abstract

2582 Background: The nontaxane microtubule dynamics inhibitor, eribulin mesylate (E7389), has a novel mechanism of action and is in development for the treatment of metastatic breast cancer, lung cancer, and other solid tumors. The objective of this study was to evaluate the effect of hepatic impairment on the pharmacokinetics of eribulin. Methods: This phase I, open-label, parallel-group study recruited adult patients with advanced solid tumors that progressed after standard therapy or for which no standard therapy existed. Patients with normal hepatic function (n=6), mild (Child-Pugh A, n=7) or moderate (Child-Pugh B, n=4) hepatic impairment received eribulin mesylate on day 1 at respective intravenous (IV) doses of 1.4, 1.1, and 0.7 mg/m2 respectively. Plasma samples were collected over 168 hr post dose for pharmacokinetic analysis. Safety was also assessed. Results: Hepatic impairment decreased clearance (4.57, 2.75, and 1.96 L/hr for normal, mild and moderate hepatic impairment, respectively) and prolonged elimination half-life (36.1, 41.1, 65.4 L/hr for normal, mild and moderate hepatic impairment). The mean dose- normalized Cmax for eribulin was comparable between patients with normal and mildly impaired hepatic function (72 vs. 84 ng/mL/mg, ratio estimate 1.1 [90% CI 0.8-1.6]), but moderate hepatic impairment increased Cmax 1.5-fold (111 ng/mL/mg, 90% CI 1.0-2.2). Eribulin exposure was increased in patients with mild and moderate hepatic impairment. The mean dose-normalized AUC(0-∞) increased 1.7-fold (420 ng.hr/mL/mg, 90% CI 1.2-2.7) and 2.8-fold (720 ng.hr/mL/mg, 90% CI 1.7-4.5), compared with patients with normal hepatic function (229 ng.hr/mL/mg). Overall, the most common treatment-emergent adverse events (TEAEs) were alopecia (n=7), nausea (n=5) and fatigue (n=4). AEs probably related to treatment included neutropenia (n=3) and peripheral neuropathy (n=1). Most of the former (3 of 4) resolved without dose reduction. The highest incidence of AEs was reported in patients with mild hepatic impairment. No deaths, treatment-related serious AEs, or discontinuations were reported. Conclusions: Eribulin exposure increased with decreasing hepatic function. Eribulin was generally safe and well tolerated. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Eisai