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Eribulin, Child-Pugh score, and liver-function tests: lessons from pivotal breast cancer studies 301 and 305
Iain R Macpherson1, Yaohua He2, Carlo Palmieri3,4
1Institute of Cancer Sciences, CR-UK Beatson Institute, University of Glasgow, Glasgow, UK.
Insights
Eribulin dosing for metastatic breast cancer patients with liver impairment should be guided by liver function tests (LFTs), not Child-Pugh scores. Elevated bilirubin levels indicate increased toxicity and dose modification needs.
Area of Science:
- Oncology
- Pharmacology
- Clinical Medicine
Background:
- Current eribulin dosing for hepatic impairment relies on Child-Pugh score, based on limited pharmacokinetic data.
- Pivotal metastatic breast cancer studies used liver function tests (LFTs) for dose adjustments, not Child-Pugh scores.
- Metastatic infiltration is a common cause of liver impairment in these patients, making Child-Pugh scores potentially less relevant than LFTs.
Purpose of the Study:
- To investigate the impact of abnormal baseline LFT results on eribulin efficacy and safety.
- To propose an alternative dosing scheme for eribulin in patients with hepatic impairment.
Main Methods:
- A pooled post hoc analysis of 1062 patients from eribulin studies (301 and 305) was conducted.
- Patients were categorized into four groups based on LFT results (normal, AST/ALT elevation, hypoalbuminemia/AST/ALT elevation without hyperbilirubinemia, and hyperbilirubinemia).
- Analysis included drug exposure, dose intensity, and treatment-emergent adverse events (TEAEs), with subcategorization by presence of liver metastases.
Main Results:
- Eribulin dosage varied by LFT group, with lower mean dosage in the hyperbilirubinemia group (0.65 mg/m²/week).
- The hyperbilirubinemia group experienced shorter treatment duration, more dose reductions/delays, and more TEAEs leading to dose modifications.
- TEAE rates leading to dose modification were significantly higher in the hyperbilirubinemia group when liver metastases were present (91.3%) compared to other groups (41.7-54.3%).
Conclusions:
- Mild elevations in bilirubin levels are linked to increased toxicity and a greater need for eribulin dose modifications.
- A novel dosing scheme based on LFTs, rather than Child-Pugh score, is proposed for eribulin in metastatic breast cancer patients with hepatic impairment.
- This LFT-based approach may optimize eribulin treatment in patients with liver dysfunction.
Background:
The recommended starting dose of eribulin in patients with hepatic impairment is based on the Child-Pugh score, largely informed by a pharmacokinetic study of 18 patients. In the pivotal studies of eribulin in metastatic breast cancer (Study 301 and Study 305 [EMBRACE]), entry criteria and dose modifications were based on liver-function test (LFT) results rather than Child-Pugh score. In populations such as patients with metastatic breast cancer, in which metastatic infiltration is the predominant cause of hepatic impairment, using Child-Pugh score may be problematic; in clinical practice, it has been more common for oncologists to make dosing decisions based on LFTs. To address this, the effects of abnormal baseline LFT results on eribulin efficacy and safety were investigated.
Methods:
In this pooled post hoc analysis, 1062 patients who were randomized to receive eribulin in Studies 301 and 305 were divided into 4 groups: (A) no elevated LFT results (no liver impairment); (B) increased levels of aspartate aminotransferase and/or alanine aminotransferase; (C) decreased albumin and/or increased levels of aspartate aminotransferase and/or alanine aminotransferase but not increased bilirubin; and (D) increased bilirubin. Patients were subcategorized by presence of liver metastasis. Drug exposure, dose intensity, and treatment-emergent adverse events (TEAEs) were analyzed.
Results:
Eribulin mesylate mean dosage was 0.82 (group A)-0.65 mg/m2/week (group D). Group D had shorter treatment, more dose reductions/delays, more TEAEs leading to dose modifications, and numerically lower objective response rates and clinical benefit rates versus groups A-C. TEAE rates leading to dose modification were similar between group D (45.5%) and groups A-C (range, 43.5-54.9%) in the absence of liver metastases, but higher in group D (91.3%) compared with groups A-C (range, 41.7-54.3%) if liver metastases were present.
Conclusions:
Mild elevations in bilirubin levels were associated with increased toxicity and a greater requirement for dose modifications. Based both on these study data and existing recommendations, we propose a novel scheme to guide initial dose selection in patients with metastatic breast cancer and hepatic impairment that is based on LFTs rather than Child-Pugh score.
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