Phase I Clinical Pharmacokinetic Study Of Docetaxel Lipid Microsphere For Injection In Patients With Advanced Cancer

Docetaxel lipid microsphere (DT-LM) for injection, which is an intravenous lipid emulsion for docetaxel without Tween-80, is a novel nanoformulation showing versatile advantages over conventional dose forms. The primary objective of this first-in-human (FIH) study was to assess the phase â…  clinical pharmacokinetic profile of DT-LM injection. Secondary objective was to compare the pharmacokinetic profiles between DT-LM injection and conventional docetaxel injection (Taxotere), and investigate the safety and tolerability. Results of present study were utilized to optimally guide the choice of the recommended phase â…¡ dose, and provide a considerable mirror for clinical pharmacokinetic study of other lipid emulsion injections.Chapter1:Backgrounds of DT-LM injection. The introvenous DT-LM was prepared and optimized in terms of preformulations, preparation processes and quality evaluations. The antitumor mechanisms of this novel formulation of docetaxel were in line with Taxotere. Results of preclinical pharmacology showed that toxicity of DT-LM was less than that of Taxotere. Both formulations were bioequivalent with respect to systemic exposure and Cmax.Chapter2:Development and validation of a rapid and sensitive UPLC-MS/MS method for determination of total docetaxel from a lipid microsphere formulation in human plasma. The previously reported bioanalytical methods had obvious shortcomings: higher LLOQ, lower sensitivity, time-comsuing preparation, longer analytical time as well as limited to conventional formulation. We had firstly developed a rapid, sensitive, accuracy and reproducible UPLC-MS/MS method to determine total docetaxel in human plasma. Validations were fully conducted according guidances of bioanalytical method validation issused by CFDA and FDA. The method is now successfully applied to a Phase I clinical pharmacokinetic study of DT-LM for injection in patients with advanced cancer.Chapter3:Development and validation of an ultrafiltration-UPLC-MS/MS method for rapid quantification of unbound docetaxel in human plasma. An optimized ultrafiltration combined with UPLC-MS/MS method was developed and validated according to guidance of bioanalytical method validation. This method has been applied to determine unbound docetaxel in human plasma after i.v. administration of DT-LM at dose of60mg/m2. Results of this part had been submitted for a domestic patent.Chapter4:Clinical pharmacokinetic study of docetaxel lipid microsphere for injection in patients with advanced cancer. The single and multiple pharmacokinetic studies were simultaneously conducted in this randomized, control, open label and single center phase I trial. A total of19patients were enrolled and given DT-LM or Taxotere. The concentrations of total docetaxel were determined using previously validated UPLC-MS/MS method. The concentration-time curve declined biphasicly from maximum concentration. The mean AUC, Tmax, Cmax and half-life time (ti/2) values of DT-LM group were higher than those of Taxotere group. The mean AUCo-t and Cmax values increased more than dose proportionally for all dose cohorts of Taxotere group. The maximum tolerability dose (MTD) was60mg/m2. Results of safety and pharmacokinetics will be utilized for declaring the recommended phase â…¡ dose.