Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin

Abstract

AIMEribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved for treatment of metastatic breast cancer. The aim of this study was to determine the effect of rifampicin, a CYP3A4 inducer, on the plasma pharmacokinetics of eribulin in patients with solid tumours. METHODSAn open-label, non-randomized phase I study was carried out. Patients received intravenous 1.4 mg m -2 eribulin mesylate on days 1 and 15 and oral rifampicin 600 mg on days 9 to 20 of a 28 day cycle. Pharmacokinetic sampling for determination of eribulin plasma concentrations was performed up to 144 h following administration. AUC(0,•) and Cmax for eribulin exposure without or with co-administration of rifampicin were subjected to an analysis of variance (ANOVA) and corresponding 90% confidence intervals (CI) were calculated. Subsequently, patients were allowed to continue eribulin mesylate treatment with 1.4 mg m -2 eribulin mesylate on days 1 and 8 of a 21 day cycle. Also the adverse event profile and anti-tumour activity were assessed. RESULTSFourteen patients were included and 11 patients were evaluable for pharmacokinetic analysis. Co-administration of rifampicin had no effect on single dose exposure to eribulin (geometric least square means ratio: AUC(0,•) = 1.10, 90% CI 0.91, 1.34 and Cmax = 0.97, 90% 0.81, 1.17). The most common treatment-related grade Ն3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%). CONCLUSIONSThese results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that was recently approved by the European Medicines Agency as monotherapy indicated for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least two chemotherapeutic regimens for advanced disease.• Preclinical data in human liver microsomes indicated that eribulin is predominantly cleared by hepatic metabolism in vitro and that CYP3A4 is the major enzyme involved.• The aim of this study was to explore the effect of repeated oral administration of rifampicin, a potent model CYP3A4 inducer, on the plasma pharmacokinetics of eribulin mesylate administered by intravenous infusion. WHAT THIS STUDY ADDS• Co-administration of rifampicin had no effect on single-dose exposure to eribulin.• These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.

Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program

“…Hence, the PPTP results in SCID mice are similar to those previously reported for eriubulin. The systemic exposure in humans at the 1.4 mg/m 2 dose is approximately 790 ng hour/ml . The number of doses of eribulin administered per treatment course for preclinical testing is three (i.e., Q4Dx3 repeated at Day 21), while in the clinic two doses are administered per course (Day 1 and 8 of each 21‐day course).…”

Primary Culture of Undifferentiated Pleomorphic Sarcoma: Molecular Characterization and Response to Anticancer Agents

“…Cells were allowed to recover for 3 days, and were then treated. Drug regimens were selected according to the plasma peak concentration of each drug from pharmacokinetic clinical data; epirubicin 2 µg/mL (Accord Healthcare Italia Ltd., Milan, Italy) plus ifosfamide 100 µM (Baxter Ltd., Rome, Italy) [ 54 , 55 , 56 , 57 , 58 ], doxorubicin 4 µg/mL (Accord Healthcare Italia Ltd., Milan, Italy) [ 57 ], 371 ng/mL eribulin (Eisai Ltd., Milan, Italy) [ 22 , 59 ], trabectedin 17 ng/mL (PharmaMar Ltd., Milan, Italy) [ 60 ], and dacarbazine 8 ug/mL (Medac Pharma Ltd., Rome, Italy) [ 61 ]. Survival percentages were assessed, as previously reported [ 62 ], by MMT assay (Sigma Aldrich) after drug exposure for 72 h. Experiments were performed twice.…”

Phase I dose-finding study of eribulin and capecitabine for metastatic breast cancer: JBCRG-18 cape study

“…On the other hand, metabolism of eribulin is very limited and the drug is mainly excreted in faeces with more than 60% as the unchanged form [ 30 ]. No drug–drug interaction with CYP3A4 inducers/inhibitors on eribulin clearance was observed in humans, although CYP3A4 has a metabolic activity on eribulin [ 31 , 32 ]. Thus, drug–drug interactions are not expected with eribulin and capecitabine.…”