Eribulin dosing in patients with advanced solid tumors and hepatic impairment.

Abstract

2544 Background: Eribulin mesylate (E7389) inhibits microtubule dynamics by a novel mechanism of action. The effects of hepatic impairment on eribulin exposure following a single intravenous administration in patients (pts) with advanced solid tumors were investigated in a Phase I study. Data from 7 Phase I and one Phase II study were used to develop population pharmacokinetic/adverse event (PK/AE) models. Methods: In the Phase I study (NCT00706095), pts were grouped by hepatic function: normal (n=6), mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=4) impairment, and received 1.4, 1.1 and 0.7 mg/m2 eribulin mesylate, respectively. Blood samples were collected post-dose over 144 hours. Log-transformed dose-normalized AUC and Cmax values were analyzed using analysis of variance. For PK modeling (n=269), eribulin mesylate dosing range was 0.1-4 mg/m2 bolus or 1 hour infusion once every 3 weeks in a 21-day cycle or once weekly for 3 weeks in a 28-day cycle. Non-linear mixed effects modeling (NONMEM) was used for model development. PK/AE models correlated the probability of a pt experiencing neutropenia with individual exposure. Results: In pts with mild and moderate hepatic impairment, mean dose-normalized AUC(0-∞) was 1.75-fold (90% CI 1.16, 2.65) and 2.79-fold (90% CI 1.72, 4.51), respectively, compared with normal function. A 3-compartment model with linear elimination described PK profiles. Clearance was significantly affected by body weight, serum albumin, alkaline phosphatase, and bilirubin. The probability of experiencing Grade 4 neutropenia increased with eribulin exposure and plasma aspartate transaminase, and was higher in pts with moderate impairment, but reduced from 22 to 15% in pts receiving 0.7 mg/m2 compared with 1.4 mg/m2 eribulin mesylate. Simulations of expected AUC values showed that this dose reduction for moderate impairment led to similar eribulin exposure in pts with normal function. Eribulin was generally well tolerated. Conclusions: Hepatic impairment decreased clearance, prolonged elimination half-life, and increased exposure to eribulin in pts with advanced solid tumors. The population PK/AE model supports eribulin mesylate dose reduction to 0.7 mg/m2 in pts with moderate hepatic impairment.