Investigational New Drugs

, Volume 31, Issue 2, pp 381–389 | Cite as

Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole

  • L. A. Devriese
  • M. Mergui-Roelvink
  • J. Wanders
  • A. Jenner
  • G. Edwards
  • L. Reyderman
  • W. Copalu
  • F. Peng
  • S. Marchetti
  • J. H. Beijnen
  • J. H. M. SchellensEmail author


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/m2 eribulin mesylate alone or 0.7 mg/m2 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.


Pharmacokinetics Drug-drug interaction Ketoconazole CYP3A4 induction Eribulin mesylate Microtubule dynamics inhibitor 



This study was funded by Eisai Ltd. Part of this study was presented in poster format at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Berlin, Germany, November 16–19, 2010 (abstract 574).

J.W., A.J. and W.C. were formerly employed by Eisai Ltd. G.E. was paid by Eisai Ltd. for statistician consultancy services. L.R. and F.P. are employees of Eisai Inc. The institute of J.H.B. has received funds for research from Eisai. All remaining authors have declared no conflicts of interest.


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • L. A. Devriese
    • 1
    • 2
  • M. Mergui-Roelvink
    • 2
  • J. Wanders
    • 3
  • A. Jenner
    • 3
  • G. Edwards
    • 3
  • L. Reyderman
    • 4
  • W. Copalu
    • 3
  • F. Peng
    • 4
  • S. Marchetti
    • 2
  • J. H. Beijnen
    • 5
    • 6
  • J. H. M. Schellens
    • 1
    • 2
    • 5
    • 7
    Email author
  1. 1.Division of Experimental TherapyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Eisai LtdHatfieldUK
  4. 4.Eisai IncWoodcliff LakeUSA
  5. 5.Science Faculty, Department of Pharmaceutical SciencesUtrecht UniversityUtrechtThe Netherlands
  6. 6.Department of Pharmacy & PharmacologySlotervaart HospitalAmsterdamThe Netherlands
  7. 7.Division of Experimental Therapy and Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands

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