Population Pharmacokinetics Of Intravenou Busulfan In Patient Received Allogeneic Hematopoietic Stem Cell Transplation And Its Models Predictive Ability Assessment

Objectives:(1)To evaluate the correlation between intravenous infusion of busulfan(IVBU)exposure and the clinical effect after transplantation in allogeneic hematopoietic stem cell transplant recipients.(2)To construct a population pharmacokinetic model of IVBU in patients with allogeneic hematopoietic stem cell transplantation in China,to quantitatively investigate the pathophysiological and biochemical indexes that influence the pharmacokinetics of IVBU,drug combination and disease types,and to verify the pharmacokinetic model of IVBU population In order to provide theoretical support for the formulation of IVBU individualized dosing regimen.Methods:(1)The clinical data of 60 patients hospitalized with allogeneic hematopoietic stem cell transplantation were collected.Using 1,5-pentanediol dimethanesulfonate as the internal standard,pre-column derivatization HPLC(120cases).The area under the IVBU drug-time curve(AUC)was estimated by the finite sampling method model established previously by the research group.The AUC value of IVBU was statistically analyzed with that of allogeneic hematopoietic stem cell transplantation Clinical efficacy,the relationship between the relevant toxicity.(2)Data of 531 blood plasma concentration monitoring data from 95 patients with allogeneic hematopoietic stem cell transplantation were retrospectively collected.The patients were randomly divided into modeling group(n = 65)and validation group(n= 30).NONMEM method was used to investigate the influence of fixed and random factors such as age,sex,actual body weight,body weight,liver and kidney function index,disease types,and combination effects on the pharmacokinetic parameters of BU,To establish a pharmacokinetic model of IVBU population in patients with allogeneic hematopoietic stem cell transplantation.The diagnostic graphs were used to evaluate the fitness of the model curve fitting.The reliability and stability of the final model were evaluated by bootstrap method.(NPDE),visual predictive test(VPC)and external validation were used to evaluate the predictive performance of the final model.Based on the established pharmacokinetics model of IVBU population,Bayesian feedback method was used to predict individual pharmacokinetic parameters,Design clinical individualized dosing regimen.Results:(1)The median AUC0-6h of IVBU in 60 recipients of allogeneic hematopoietic stem cell transplantation was 703.13(510.99-1382.24)μmol · min /L.The rate of hematopoietic implantation,the incidence of acute graft-versus-host disease and overall survival were 96.7%,38.3% and 95%,respectively.Oral mucositis,gastrointestinal reactions,hepatic veno-occlusive syndrome,hemorrhagic cystitis,cytomegalovirus infections,pulmonary infections,impaired liver function,impaired renal function,and CNS lesions over 100 days after transplantation The incidence rates were 31.7%,30%,3.3%,28.3%,45%,38.3%,5%,2% and 3.3% respectively.Oral mucositis,the severity of acute graft-versus-host disease and the incidence of hepatic vein occlusive syndrome were positively correlated with IVBU plasma AUC.When transplanted patients with IVBU plasma AUC0-6h within 900-1300μmol · min/ L can achieve good clinical efficacy,AUC values above or below the range will lead to increased patient mortality.(2)The pharmacokinetics model of IVBU population was established based on 471 plasma concentrations and related information of 65 patients with allogeneic hematopoietic stem cell transplantation.The change of IVBU in vivo was in accordance with the two-compartment model.The final model formula was:CL(L / h)= 11.9 ×(WT / 70)0.856 × 1.28 SEX V1(L)= 40.1 ×(WT / 70)1.15Q(L / h)= 25.1V2(L)= 26.9Typical values for CL and V1 are 10.8 L / h and 31 L respectively.The diagnostic results showed that the pharmacokinetic model of IVBU final population was stable and reliable and the accuracy was better than that of the basic model.The success rate of Bootstrap method was 92.8%,and the estimation of population parameters fell within 95% confidence interval of Bootstrap’s estimation results.In the blue range, the figure is basically normal distribution;MDPE = 18.86% and MDAE = 21.45% in the final validation of the external validation model.The prediction accuracy of the final model is higher than that of the basic model.Conclusion:(1)The AUC value of IVBU is closely related to the graft-related toxicity.To monitor the blood concentration of BU in patients with allogeneic hematopoietic stem cell transplantation and to adjust the systemic exposure of drugs,it is helpful for the clinical treatment and reduction of allogeneic hematopoietic stem cell transplantation patients The incidence of postoperative complications related to transplantation.(2)The population pharmacokinetic model of IVBU in patients with allogeneic hematopoietic stem cells has been successfully established in this study.The model is stable and effective with both internal and external validation.It has good predictive performance and can provide IVBU for allogeneic hematopoietic stem cell transplantation patients.Individualized dosing regimen will help to improve the clinical effect of drug treatment and avoid the occurrence of adverse drug reactions.