title: Eribulin mesylate pharmacokinetics in patients with solid tumors receiving repeated oral ketoconazole.
abstract: 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.
authors.affiliation: Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Devriese
authors.forename: M
authors.initials: M
authors.lastname: Mergui-Roelvink
authors.forename: J
authors.initials: J
authors.lastname: Wanders
authors.forename: A
authors.initials: A
authors.lastname: Jenner
authors.forename: G
authors.initials: G
authors.lastname: Edwards
authors.forename: L
authors.initials: L
authors.lastname: Reyderman
authors.forename: W
authors.initials: W
authors.lastname: Copalu
authors.forename: F
authors.initials: F
authors.lastname: Peng
authors.forename: S
authors.initials: S
authors.lastname: Marchetti
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000935:Antifungal Agents / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005663:Furans / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007654:Ketoconazole / Q000008:administration & dosage*; D007659:Ketones / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D014018:Tissue Distribution; D000095662:Polyether Polyketides
chemical_list: D000935:Antifungal Agents; D005663:Furans; D007654:Ketoconazole; D007659:Ketones; C490954:eribulin; D000095662:Polyether Polyketides