lu-224332 and Lung-Neoplasms

Felotaxel (SHR110008), currently under clinical investigation in phase I trial, is a new effective taxane with greater anticancer activity and less toxicity than docetaxel. Pharmacokinetic studies in animal models are the important components in clinical development of this agent. In this study, a rapid and sensitive analytical method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of felotaxel in tumor-bearing mice plasma, urine, feces and tissues (brain, heart, liver, lung and kidney and tumor). For all matrices, sample preparation involved liquid-liquid extraction with ethyl acetate. Calibration curves (1/x² weighted) offered satisfactory linearity (r² ≥ 0.995) within the test range. The lower limit of quantitation (LLOQ) for all matrices was 10 ng/ml except that for mouse plasma and brain LLOQ was 1 ng/ml. The accuracy and precision ranged from 86.1 to 107.2% and 1.1 to 9.2%, respectively. Recoveries (73.9-96.1%) and matrix effects (76.4-97.2%) were satisfactory in all the biological matrices examined. Stability studies (85.1-101.5%) showed that felotaxel was stable both during the assay procedure and long-term storage. The assay was successfully applied to plasma pharmacokinetics, tissue distribution and excretion study of mice. The pharmacokinetic parameters, such as half-life, mean residence time, maximum concentration were determined. The preclinical data are useful for the design of clinical trials of felotaxel.

Topics: Animals; Antineoplastic Agents; Chromatography, Liquid; Diazepam; Drug Stability; Lung Neoplasms; Male; Mice; Mice, Nude; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry; Taxoids; Tissue Distribution; Xenograft Model Antitumor Assays