Population pharmacometric analyses of eribulin in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

Abstract

Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose-independent, three-compartment model with allometric relationship for body weight, was similar for all tumor types. Inter-individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulin's effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure-efficacy relationships to inform physicians treating patients with MBC.

Pharmacodynamic analysis of eribulin safety in breast cancer patients using real‐world postmarketing surveillance data

“…The population pharmacokinetic (PK)/pharmacodynamic (PD) model for eribulin is shown in Figure . Plasma eribulin concentrations were simulated based on a population PK model developed by Majid et al, who reported that eribulin PK could be described by a three‐compartment model with linear elimination from the central compartment and overall steady‐state exposure (area under the curve) that increased proportionally with the total eribulin dose. The following PK parameters were calculated from the Majid et al population PK model using individual patient demographic data to simulate the PK profile: clearance (CL [L/h]), volume of compartments (V1, V2 and V3 [L]), and intercompartmental clearance (Q2 and Q3 [L/h]).…”

“…The population pharmacokinetic (PK)/pharmacodynamic (PD) model for eribulin is shown in Figure 1. Plasma eribulin concentrations were simulated based on a population PK model developed by Majid et al, 11 who reported that eribulin PK could be described by a three-…”

A Review of Mathematical Models for Tumor Dynamics and Treatment Resistance Evolution of Solid Tumors

“…Eq. 22 22,25 Exposure-dependent treatment effect with resistance (TGI model) 20,48,49 Introducing a damaged cell compartment…”

Systemic Treatment Approaches in her2-Negative Advanced Breast Cancer—Guidance on the Guidelines

“…In patients with prior exposure to anthracycline, taxane, and capecitabine, there is evidence for treatment with eribulin 53,54 or ixabepilone 55,56 . In patients who prefer to avoid or reduce the risk of alopecia, capecitabine, vinorelbine, or gemcitabine can be chosen.…”