Population Pharmacokinetics Of Intravenous Busulfan In Patients Undergoing Hematopoietic Stem Cell Transplantation Based On Genetic Polymorphisms Of Drug Transporter And Metabolic Enzymes

ObjectivesTo establish the population pharmacokinetic model of intravenous busulfan in Chinese patients undergoing hematopoietic stem cell transplantation based on genetic polymorphisms of drug transporter and metabolic enzymes and provide reference for individualized TherapyMethod1.To genotype GSTTland GSTMI by using Multiple PCR.2.To genotype the SNPs of drug transporters and metabolic enzymes related to busulfan by using MALDI-TOF-MS3.To determine the blood concentration of busulfan by using HPLC-MS/MS4.To builde population pharmacokinetic model through nonlinear mixed effect model method with Phoenix NLME after investigating all data of HSCT patients related to demography,pathophysiology and polymorphisms of drug transporter and metabolic enzymes5.To evaluate the goodness of fit by plot;to evaluate the internal validity by Bootstrap and the predictive ability by VPCResults1.The distribution frequency of GSTT1(+)and GSTT1(-)were 58.1%and 41.9%in 93 HSCT patients,respectively2.The distribution frequency of GSTM1(+)and GSTM1(-)were 58.1%and 41.9%3.The genetype distribution frequencies(wild homozygous/heterozygous/homoz-ygosis mutations)of the SNPs related to busulfan were:ABCB1 rs1045642(39.8%/46.2%/14.0%);CTH rs482843(61.3%/34.4%/4.3%);CTH rs1021737(60.2%/30.1%/9.7%);CYP3A4 rs2242480(58.1%/34.4%/7.5%);CYP3A5 rs776746(43.0%/44.1%/12.9%);DPEP1 rsll26464(54.8%/35.5%/9.7%);FMO3 rs2266782(61.3%/32.3%/6.5%);GSTA1 rsll964968(1.1%/76.3%/22.6%);GSTA1 rs3957357(81.7%/18.3%/0.0%);GSTA1 rs4715333(66.7%/33.3%/0.0%);GSTA1 rs58912740(75.3%/24.7%/0.0%);GSTA2 rs2180314(47.3%/48.4%/4.3%);GSTA2 rs6577(61.3%/30.1%/8.6%);GSTA3 rs15032(95.7%/4.3%/0.0%);GSTA4 rs7496(64.5%/30.1%/5.4%);GSTA5 rs4715354(58.1%/38.7%/3.2%);GSTK1 rs1917760(65.6%/32.3%/2.2%).Distributions of all SNPs except rs11964968 were in Hardy-Weinberg equilibrium.4.The final model based on 381 concentrations of 93 patients was as follow:CL=10.280×(BSA/1.548)0.951 ×e0.0471 When rs58912740(GSTA1)1s wild homozygous:V=38.097×(BSA/1.548)1.332×e0.0474 When rs58912740(GSTA1)is heterozygous:V=38.097×(BSA/1.5483)1.332×e0.199×e0.04745.The scatter grams showed that the final model had a better goodness of fit and smaller individual variations when compared with the Base Model.The steady rate was 100%and relative deviation was less than 4.5%according to Bootstrap,all estimates of Final Model were in 95%Cl of the estimates of Bootstrap.VPC showed that the final model had a good predictive capacity.Conclusions1.The modified Multiple PCR method developed in this study for genetyping GSTT1 and GSTMI is simple,stable and reliable,it is suitable for DNA samples with low concentration.2.MALDI-TOF-MS shows advanced high efficiency,sensitivity and accuracy,which 1s appropriate for genetyping the SNPs of transporter and metabolic enzymes related to Bu.3.The PPK model established in this study shows good stability and predictive capacity,which can provide reference for individualized therapy.