| OBJECTIVEDocetaxel (DTX) submicron emulsion injection is a novel o/w formulation that is prepared by high-pressure homogenization in which the long-chain and medium chain triglycerides is oil phase, the refined lecithin is emulsifier and glycerol is isotonic regulator. In the present study, we evaluated the pharmacokinetics of DTX submicron emulsion injection in beagle dogs, compared the pharmacokinetic parameters with DTX injection (Taxotere(?)) as well, providing an experimental basis for evaluation of pharmacodynamics and safety as well as the dosage regimen applicated in Phase I clinical research.METHODS1. Physical properties evaluation of DTX submicron emulsion injectionThe form of submicron emulsion is observed by transmission electron microscopy. The particle size, size distribution and Zeta potential value are determined by Malvern nm diameter and potential analyzer.2. Development and Validation of a Liquid Chromatography Tandem Mass Spectrometry Assay for the Quantification of DTX in Beagle dog plasmaThe assay uses paclitaxel as the internal standard for docetaxel and a simple liquid-liquid extraction procedure.3. Pharmacokinetics Study of DTX submicron emulsion injection in beagle dogs on different dose levelThe pharmacokinetics study in six health beagle dogs (3 males and 3 females) was based on a single-dose, randomized, three-period crossover design. DTX submicron emulsion injection 10 mg/m2,20 mg/m2 or 40 mg/m2 were administered as a 1 h i.v. infusion every 3 weeks. The blood samples of about 3 mL were collected from the posterior leg vein into heparinized centrifuge tubes at different time. DTX analysis in plasma was done by HPLC-MS/MS and the date was fit by DAS 2.1 to calculate the pharmacokinetics parameters. Statistical analysis was carried out using the statistical package for social science (SPSS).4. Pharmacokinetics Study in beagle dogs with DTX submicron emulsion injection and Taxotere(?)The pharmacokinetics study in six health male beagle dogs was based on a single-dose, randomized, two-period crossover design. DTX submicron emulsion or Taxotere(?) 20 mg/m2 were administered as 1 h i.v. infusion every 3 weeks. The blood samples of 3 mL were collected from the posterior leg vein into heparinized centrifuge tubes at different time. DTX analysis in plasma was done by HPLC-MS/MS and the date was fit by DAS 2.1 to calculate the pharmacokinetics parameters. Statistical analysis was carried out using the statistical package for social science (SPSS).RESULTS1. Physical properties evaluation of DTX submicron emulsion injectionThe particle size and Zeta potential value are 226.2±10.7 nm,-25.4±0.25 mv, relatively.2. Development and Validation of a Liquid Chromatography Tandem Mass Spectrometry Assay for the Quantification of DTX in Beagle dog plasmaThe calibration curve for DTX was linear over the range 3.286～821.6μg·L-1 and the LLOQ was 3.286μg·L-1. The intra-and inter-day coefficient of variation were less than 8.0% and the recovery of DTX was range from 96.1%～111.5%. The method was consistent with demands of biological samples analysis in pharmacokinetics research.3. Pharmacokinetics Study of DTX submicron emulsion injection in beagle dogsIn the single dose study, the main pharmacokinetic parameters of DTX were as follows:At the dose of 10 mg/m2, Cmax was 262.16±42.13μg·L-1, tmav was 1 h, AUC0-t was 241.68±25.59μg·L-1·h, t1/2 was 3.72±3.19 h, CLwas 39.07±4.78 L·h-1·m-2, V was 201.75±172.02 L·m-2. At the dose of 20 mg/m2, Cmax was 476.74±84.84 mg·L-1, tmax was 1 h, AUC0-t was 461.65± 82.40 mg·L-1·h, t1/2 was 7.54±4.43 h, CL was 44.56±8.19 L·h-1·m-2, V was 484.56±290.06 L·m-2. At the dose of 40 mg/m2:Cmax was 1028.37±156.32 mg·L-1, tmax was 1 h, AUC0-t was 931.86±113.21 mg·L-1·h, t1/2 was 12.17±8.04 h, CL was 41.35±6.01 L·h-1·m-2, V was 696.95±395.25 L·m-2.4. Pharmacokinetics Study in beagle dogs with DTX submicron emulsion injection and Taxotere(?)The main pharmacokinetic parameters of DTX submicron emulsion injection were as follows:Cmax was 466.71±73.14μg·L-1, tmax was 1 h, AUC0-t was 451.94±43.91μg·L-1·h, t1/2 was 4.40±0.51 h, CL was 42.62±3.68 L·h-1·m-2, V was 270.88±43.60 L·m-2.The main pharmacokinetic parameters of Taxotere(?) were as follows:Cmax was 510.06±168.58μg·L-1, tmax was 1 h, AUC0-twas 476.79±96.19μg·L-1·h, t1/2 was 5.76±4.24 h, CL was 40.99±9.59 L·h-1·m-2, V was 299.45±146.51 L·m-2.CONCLUSIONS1. In the single doses range from 10 mg/m2 to 40 mg/m2, DTX submicron emulsion injection exhibited linear pharmacokinetics processes in beagle dogs.2. DTX submicron emulsion injection and Taxotere(?) had similar pharmacokinetics processes in beagle dogs. |
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