Population pharmacokinetics (PPK) of eribulin mesylate in patients with locally advanced or metastatic breast cancer (MBC)

Abstract

2524 Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mechanism of action. A study was conducted to evaluate efficacy, safety and pharmacokinetics of eribulin at a dose of 1.4 mg/m2 for locally advanced or MBC in patients previously treated with an anthracycline, a taxane, and capecitabine. Methods: Eribulin was administered intravenously over 2–5 minutes at a dose of 1.4 mg/m2 on days 1 and 8 of a 21- day cycle to 291 patients. Four plasma samples were collected between 5 min and 120 hours after the first dose. Plasma eribulin concentrations were determined by LC/MS/MS. A total of 774 samples, from 209 patients with complete dose and sampling information were included in the PPK analysis, which was conducted using nonlinear mixed effects modeling (NONMEM). Results: Eribulin PKs were best described by a three-compartment model, with elimination from the central compartment. Distribution was rapid and elimination slow. For a typical patient with AST<ULN and CLCR=101mL/min (Cockroft-Gault), clearance (CL) was 2.98 L/h and central volume of distribution 3.72 L (V1). Volumes and inter-compartmental clearances for the two peripheral compartments were 3.60 L (V2), 126 L (V3), 2.7 L/h (Q2) and 5.6 L/h (Q3). Inter-patient variability on CL was 57%, and ranged from 26- 98% for other parameters. Residual error was 21% (proportional). CL was on average 38% lower in patients with AST>ULN and positively correlated with renal function. The covariate effects only explained a minor fraction of inter-patient variability in this single study dataset. Conclusions: Eribulin PKs were described by a three-compartment model with rapid distribution and slow elimination. Appreciable interpatient PK variability exists, a minor fraction of which was explained by measures of liver and renal function. [Table: see text]