TY - JOUR
T1 - Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole.
AU - Devriese, L.A.
AU - Mergui-Roelvink, M.
AU - Wanders, J.
AU - Jenner, A.
AU - Edwards, G.
AU - Reyderman, L.
AU - Copalu, W
AU - Peng, F.
AU - Marchetti, S.
AU - Beijnen, J.H.
AU - Schellens, J.H.M.
PY - 2013
Y1 - 2013
N2 - 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-infinity 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.
AB - 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-infinity 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.
M3 - Article
SN - 0167-6997
VL - 31
SP - 381
EP - 389
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 2
ER -