Published in:
01-04-2013 | PHASE I STUDIES
Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole
Authors:
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. Schellens
Published in:
Investigational New Drugs
|
Issue 2/2013
Login to get access
Summary
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.