Population Pharmacokinetics Of Paclitaxel In Patients With Solid Tumor

Objective1.To establish the population pharmacokinetic(PPK)model of paclitaxel(PTX)in Chinese and provide reference for individualized administration.2.To discuss the effect ofMDR1 C3435T polymorphism on pharmacokinetics parameter of PTX.Method1.HPLC method was used to determine the plamsa concentrations of paclitaxel.2.Polymerase Chain Reaction-restriction fragment length polymorphism(PCR-RFLP)was used to genotype the MDR1 C3435T polymorphisms.3.The effects of physiological and pathological,othermedication and MDR1 C3435T polymorphisms on pharmacokinetic parameter were investigated by using NONMEM to establish PPK model of paclitaxel.4.Apply the graphic to evaluate the goodness of fit and internal validity of the model was evaluate by Bootstrap.Normalized predictive distribution error(NPDE)and external validation were adopted to evaluate the predictive ability and reliability.Result1.The regression equation of standard cuve was Y = 0.0035X-0.0296(r=0.9999,n=7).The linearity was good within the range of 20～1280 ng·mL-1 and the detection limit was 10 ng-mL-1(S/N≥3).The extraction recoveries were 95.3%～112.8%and recoveries were 98.4%～105.9%.Both the intra-day and inter-day RSD was less than 6%.2.In this study,the number of the genotyping MDR1 C3435T is CC,53 cases(38.4%);CT,68 cases(68.3%);TT,7 cases(12.3%)in 138 cases of patients.Genotype distrubution was consistent with Hardy-weinberg equilibrium.3.According to 210 concentrations of the 138 patients,the PPK final model of PTX was established,as follow:CL(L· h-1)= θCL×(CLcr/98.83)θCLcr×(RATE×eηt V(L)= θ4.The scatter gram shows that the goodness of fit of the final model is better than the simple model.The steady rate was 98.25%and relative deviation was less than 3.5%verified by Bootstrap.NPDE indicates that the final model was homogeneity of variance and obey normal distribution.The external validation results shows that the final model has higher accuracy and precision than the simple model.Conlusion1.HPLC method is suitable for therapeutic drug monitoring of PTX with good accuracy,high sensitivity and convenient operation.2.The determination of genotypes of the MDR1 C3435T polymorphism by PCR-RFLP was accurate.3.The PPK model of PTX is established in the present study is of great stability and predictive ability,which could provide basis for individualized dosage regimens.