ABSTRACT
Eribulin mesylate (E7389), a tubulin and microtubule inhibitor, has been approved to treat metastatic breast cancer in certain patient populations. A liposomal formulation of E7389, E7389-LF, aims to increase the therapeutic profile of E7389. As determining the free drug concentration is crucial for the assessment of efficacy and toxicity of liposomal drug, in this study, an ultracentrifugation method coupled with LC-MS/MS was developed to separate the free E7389 from liposomal and protein bound E7389. The pharmacokinetics of the free E7389 after dosing either E7389 or E7389-LF was characterized. The concentration ratio of E7389 in ultracentrifuged mice plasma (UCM) vs E7389 in plasma after a 2mg/kg i.v. of E7389 ranged from 54.19% to 65.41%, which was similar to the free fraction in the mouse plasma. The respective concentration ratio of E7389 in UCM vs E7389 in plasma after a 2mg/kg i.v. of E7389-LF ranged from 0.07% to 0.59%, and the exposure, expressed as AUC, of UCM/plasma ratio was determined to be 0.2%. Pharmacokinetic modeling was performed to estimate the release kinetics of E7389 from E7389-LF, and the release was best described by a first order rate constant k(rel) 0.078 h(-1). Sensitivity analysis demonstrated that further decrease the release rate constant by adjusting liposome formulation would lead to decreased C(max) and much longer half-life of UCM E7389, which might result in better efficacy and lower toxicity.
Subject(s)
Furans/pharmacokinetics , Ketones/pharmacokinetics , Tubulin Modulators/pharmacokinetics , Animals , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Drug Compounding , Drug Stability , Furans/administration & dosage , Furans/blood , Injections, Intravenous , Ketones/administration & dosage , Ketones/blood , Limit of Detection , Liposomes , Male , Mice , Mice, Inbred Strains , Models, Biological , Molecular Structure , Tandem Mass Spectrometry , Time Factors , Tubulin Modulators/administration & dosage , Tubulin Modulators/bloodABSTRACT
An LC/MS/MS method was developed to quantify carboplatin and eribulin mesylate (E7389) in human plasma and urine. For carboplatin, sample clean-up by protein precipitation and supernatant injection into a Waters Spherisorb((R)) S5 SCX column was used. Liquid-phase extraction and reverse-phase chromatography on a Polaris C18 column were used for eribulin. Quantitation involved LC/MS/MS with positive electrospray ionization. Accuracy, precision, linearity, range, specificity, recovery and stability were also evaluated. Both compounds were stable in human plasma (>or=80 days at -80 degrees C), at room temperature (>or=4h), following three freeze-thaw cycles and in 50/50 methanol/H(2)O (<4 degrees C for >or=252 days).
