Pharmacokinetics of eribulin mesylate in patients with solid tumours receiving repeated oral rifampicin.
OBJECTIVE
Eribulin 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.


METHODS
An 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 C(max) 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.


RESULTS
Fourteen 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 C(max) = 0.97, 90% 0.81, 1.17). The most common treatment-related grade ≥3 adverse events were grade 3 neutropenia (4/14, 29%), leucopenia and fatigue (both 3/14, 21%).


CONCLUSIONS
These results indicate that eribulin mesylate may be safely co-administered with compounds that are CYP3A4 inducers.
Division of Experimental Therapy and Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Lot A
LA
Devriese
Petronella Els O
PE
Witteveen
Jantien
J
Wanders
Kenneth
K
Law
Geoff
G
Edwards
Larisa
L
Reyderman
William
W
Copalu
Fuping
F
Peng
Serena
S
Marchetti
Jos H
JH
Beijnen
Alwin D R
AD
Huitema
Emile E
EE
Voest
Jan H M
JH
Schellens
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D050256:Antimitotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005663:Furans / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007659:Ketones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000378:metabolism*; D012293:Rifampin / Q000008:administration & dosage*; D044465:White People; D000095662:Polyether Polyketides
D050256:Antimitotic Agents; D004791:Enzyme Inhibitors; D005663:Furans; D007659:Ketones; D012293:Rifampin; C490954:eribulin; D000095662:Polyether Polyketides