| Background and Objective:Paclitaxel is one of the most effective anti-tumor drugs in the treatment of many advanced and refractory cancers,but its poor water solubility limits its clinical application.Polymer micelles can increase the water solubility of paclitaxel and reduce the toxic and side effects of paclitaxel,and have good application prospects.The purpose of this study is to investigate the pharmacokinetics of paclitaxel polymer micelles for injection with polyethylene glycol monomethyl ether-poly(D,L-lactide)as carrier in rats and humans,and to obtain pharmacokinetic parameters,thereby providing a basis for its clinical application.Methods:Eighteen SD rats were administered paclitaxel polymer micelles at 3 mg/kg,10 mg/kg and 30 mg/kg respectively by tail intravenous injection to study its pharmacokinetics in rats.Twelve patients with advanced cancer in China participated in the pharmacokinetic study of paclitaxel polymer micelles in humans.Paclitaxel polymer micelles were administered intravenously as 3 h infusion every 21 days,and the dose was escalated from 175 mg/m2 to 300 mg/m2.Paclitaxel concentrations in rat and human plasma were determined by high performance liquid chromatography tandem mass spectrometry.The peak area of chromatography was acquired and processed by Analyst software.The non-atrioventricular model of Win Nonlin 8.3 was used to calculate the pharmacokinetic parameters.The main pharmacokinetic parameters were statistically analyzed by SPSSAU software.Results:The standard curve for paclitaxel in rat and human plasma was well linear within the range of 10.00?10000 ng/m L.The intra-assay precision and the inter-assay precision of the analytical method for paclitaxel in rat plasma were within6.0%and 9.5%,respectively,the average accuracy ranged from-8.2%to 7.7%,the matrix effect ranged from 84.8%to 90.3%,and the extraction recovery ranged from98.5%to 106.7%.The intra-assay precision and inter-assay precision of the analytical method for paclitaxel in human plasma were within 4.2%and 9.2%,respectively,the average accuracy ranged from-3.2%to 5.6%,the matrix effect ranged from 93.9%to97.1%,and the extraction recovery ranged from 90.6%to 98.6%,all of which met the relevant requirements for verification of bioanalytical methods.Paclitaxel was stable in rat and human plasma.The T1/2 of different doses of paclitaxel in rats were 4.22±0.58 h?4.80±2.62 h?3.37±1.11 h,respectively.Cmax were 361.5±38.7 ng/m L,3581±816 ng/m L and 23847±5068 ng/ml,respectively.AUC024h were 431.7±59.5h·ng/m L,4095±1262 h·ng/m L,28060±10977 h·ng/m L,respectively.The CL were5850±965 m L/h/kg,2564±794 m L/h/kg and 1175±360 m L/h/kg,respectively.The T1/2 of different doses of paclitaxel in humans were 17.35±2.88 h?21.94±1.33 h?18.63±2.91 h,respectively.Cmax were 1822±516 ng/m L,2771±1644 ng/m L and3598±842 ng/m L,respectively.AUC072h were 7288±1772 h·ng/m L,11891±5679h·ng/m L and 14871±4317 h·ng/m L,respectively.The CL were 23838±5248m L/h/m2,21084±9519 m L/h/m2 and 20844±5084 m L/h/m2,respectively.Conclusion:The established LC-MS/MS method was accurate,reliable and reproducible,and could be used for the pharmacokinetic study of paclitaxel polymeric micelles.No serious adverse reactions occurred in rats and subjects within the administered dose range,and paclitaxel polymeric micelles exhibited a non-linear pharmacokinetic profile in rats.The exposure(AUC,Cmax)increased significantly and the clearance decreased with increasing dose.There were no significant gender differences in pharmacokinetic parameters.It suggested that the dose escalation design in humans should be done with caution.The exposure of paclitaxel polymeric micelles in humans increased roughly in proportion with increasing dose.Pharmacokinetic parameters had no dose-dependent changes.Paclitaxel had longer half-life and lower clearance.The half-life was approximately four times longer than that in rats,indicating that there were species differences in pharmacokinetics between rats and humans.Paclitaxel polymeric micelles prolonged the circulation time of paclitaxel in rats and humans compared with traditional paclitaxel injection. |
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