A reduced dose of 1.1 and 0.7 mg/m(2) of eribulin mesylate is recommended for patients with Child-Pugh A or B hepatic impairment, respectively.

Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H(2)SO(4)/CH(3)CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC(50)'s > 1000 nM), but five (2, 6, 10, 11, 12) had IC(50)'s between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC(50)'s of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei-infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.

Purpose To study the influence of repeated oral administration of ketoconazole, a potent CYP3A4 inhibitor, on the plasma pharmacokinetics of eribulin mesylate administered by single-dose intravenous infusion. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor that is currently under development in phase I-III trials for the treatment of solid tumors. Experimental design A randomized, open-label, two treatments, two sequences, crossover phase I study was performed in patients with advanced solid tumors. Treatments were given on day 1 and day 15 and consisted of 1.4 mg/m(2) eribulin mesylate alone or 0.7 mg/m(2) eribulin mesylate plus 200 mg ketoconazole on the day of eribulin mesylate administration and the following day. Pharmacokinetic sampling for determination of eribulin plasma concentration was performed up to 144 h following administration of eribulin mesylate. Also safety and anti-tumor activity were determined. Results Pharmacokinetic sampling and analysis was completed in ten patients. Statistical analysis of dose-normalized log-transformed AUC0-∞ and Cmax indicated that single-dose exposure of eribulin was not statistically different when co-administered with ketoconazole (ratio of geometric least square means: 0.95 (90%CI: 0.80-1.12) and 0.97 (90%CI: 0.83-1.12), respectively) in patients with solid tumors. Ketoconazole had no effect on eribulin clearance and elimination half-life. The most frequently reported treatment related adverse events were fatigue and nausea, each reported in 8/12 patients. Seven patients (58.3 %) achieved stable disease as best overall response. Conclusions The results indicate that eribulin mesylate can be safely co-administered with ketoconazole. Drug-drug interactions are not expected with other CYP3A4 inhibitors.

Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.

1 The partitioning of diethylcarbamazine (DEC) between octan-1-ol and aqueous buffer was shown to be dependent upon the pH of the buffer. 2 Buccal absorption of DEC in five subjects was shown to increase with increasing pH. 3 In view of these findings, the disposition of DEC was investigated in the same five subjects following the oral administration of 50 mg DEC citrate on two occasions. 4 The elimination half-life (T½) of DEC and the area under the plasma concentration v time curve (AUC) were significantly increased when an alkaline urinary pH was maintained compared with the values of these parameters obtained on a second occasion when an acidic urinary pH was maintained. Renal clearance and total urinary excretion of DEC were significantly less at alkaline urinary pH than under acidic conditions. 5 The clinical significance of these observations is discussed both with respect to dose modification under conditions of changing urinary pH and the possibility ofthe manipulation ofurinary pH in order to produce more effective dosage regimens.

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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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