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A simple and sensitive method based on ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed for the determination of TM-2, which was a novel semi-synthetic taxane derivative in beagle dog plasma. Cabazitaxel was chosen as internal standard. Following extraction by methyl tert-butyl ether, the chromatographic separation was achieved on a Thermo Syncronis C18 column (50 × 2.1 mm, 1.7 µm) by gradient elution within a runtime of 3.5 min. The mobile phase consisted of (A) acetonitrile and (B) 2 mmol/L ammonium acetate in water. The detection was accomplished using positive ion electrospray ionization in multiple reaction monitoring mode. The MS/MS ion transitions were monitored at m/z 812.39 → 551.35 for TM-2 and 836.36 → 555.26 for IS, respectively. The method was linear for TM-2 (r = 0.9924) ranging from 2.5 to 1000 ng/mL. The intra-day and inter-day precisions (relative standard deviation) were within 8.0 and 17.6%, respectively, and the accuracy (relative error) was less than 2.3%. The extraction recovery ranged from 83.1 to 97.1%. The reliable method was successfully applied to a pharmacokinetic study of TM-2 in beagle dogs after intravenous drip with different doses of 0.6, 1.2, and 2.4 mg/kg, respectively.

TM-2 is a novel semi-synthetic taxane derivative, selected for preclinical development based on its greater anticancer activity and lower toxicity compared with docetaxel. In this study, a rapid and sensitive analytical method based on ultra performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of TM-2 in rat plasma. The biological samples were extracted with methyl tert-butyl ether and separated on a C18 column (50 mm × 2.1 mm, 1.7 µm) using a mobile phase consisting of acetonitrile and 2 mM ammonium acetate. The standard curves were linear over the range 5-1000 ng/mL in rat plasma. The precision (relative standard deviation, RSD, %) were within 14.5%, and the accuracy (relative error, RE, %) ranged from -1.56 to 2.36%. Recovery and matrix effect were satisfactory in rat plasma. The validated method was successfully applied to pharmacokinetic studies after intravenous administration of TM-2 to rats. The pharmacokinetics of TM-2 in rats were characterized by a large volume of distribution and a long half-life of elimination after single dose (4, 8, and 16 mg/kg), and a good correlation was observed between AUC and dose. The preclinical data will be useful for the design of subsequent trials of TM-2.

In this work, we describe the evaluation of the stability and pharmacokinetics of cabazitaxel‐loaded lipid microspheres (CTX‐LM) prepared by high‐pressure homogenization. Investigation of the physicochemical stability under different homogenization cycles and diverse sterilization times confirmed that 8 cycles at 800 bar and 121°C for 8 min were the optimal technological parameters. The beneficial effect of cholesterol on the physical stability of CTX‐LM was confirmed and its mechanism of action was identified. The stability of CTX‐LM using an aqueous isotonic glucose solution as a diluting agent was greater compared with using 0.9% NaCl solution as a result of an electric charge effect. CTX‐LM are stable under freeze‐thaw conditions and should not be exposed to high temperatures and protected from light during storage. Furthermore, all the changes in parameters were within an acceptable range at 4°C within 9 months, which supported the good long‐term stability of CTX‐LM. Finally, to compare the pharmacokinetics of CTX‐LM with cabazitaxel‐solution in vivo, a rapid, accurate UPLC‐MS/MS method was developed and used to determine cabazitaxel in rat plasma after a single intravenous administration of 4 mg/kg. An obviously larger area under the curve (AUC) of CTX‐LM was observed than that of CTX‐solution, which will improve the antitumor efficacy of cabazitaxel. Practical applications: As a novel semisynthetic taxane, cabazitaxel has shown antitumour activity in a broad range of cell‐lines and tumor models and has been approved in combination with prednisone for the treatment of patients with castration‐resistant metastatic prostate cancer. However, serious undesirable effects in humans, such as anaphylactoid hypersensitivity reactions and peripheral neuropathy were produced by the addition of polysorbate 80 to commercial products. In this paper, CTX‐LM was prepared by high‐pressure homogenization in order to overcome the above drawbacks. The good stability and markedly higher AUC of CTX‐LM may hasten their passage from a pre‐clinical phase to a clinical trial phase and allow their production on a large scale. In this paper, cabazitaxel lipid microspheres exhibited a great stability and had a higher AUC than cabazitaxel solution.