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.

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AIMSThe aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy. METHODSA multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. RESULTSFifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m À2 day À1 , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m À2 day À1for patients with moderate renal impairment (suggested dose 1.9 mg m À2 day À1 for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m À2 day À1 in this cohort. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Topotecan is a specific inhibitor of topoisomerase-I and is approved for treatment of patients with cancer.• Topotecan exposure is increased in patients with moderate and severe renal impairment after intravenous administration.• The effect of renal impairment on the toxicities and pharmacokinetics of oral topotecan in patients with advanced solid tumours is unknown. WHAT THIS STUDY ADDS• Dose-limiting toxicities were mostly haematological.• Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment.• Asian patients had higher AUCs than non-Asian patients with the same degree of renal impairment.