Population Pharmacokinetic Study Of Cyclosporine In Chinese Paediatric Aplastic Anemia Patients And Hematopoietic Stem Cell Transplant Recipients

Objective: In order to find the influence factor for the pharmacokinetic parameters ofcyclosporine in the different pupulation groups for the individualized therapy, the studyanalysised population pharmacokinetic characteristics of cyclosporine and establishedcyclosporine population pharmacokinetic models in Chinese paediatric aplastic anemiapatients and allogeneic hematopoietic stem cell transplant （allo-HSCT） recipients.Methods:（1） Cyclosporine concentrations and clinical data were obtained from94paediatric aplastic anemia patients and117allo-HSCT recipients.（2） All the patients were genotyped for CYP3A4^*1G, CYP3A5*3, ABCB1C1236T,ABCB1G2677T/A, ABCB1C3435T SNPs by polymerase chain reaction-restrictionfragment length polymorphism （PCR-RFLP）. Evaluate the effect of CYP3A4, CYP3A5and ABCB1genetic polymorphisms on the dose-adjusted concentration and doserequirement of cyclosporine in Chinese Patients with hematologic diseases.（3） The data of94paediatric aplastic anemia patients and the data of117allo-HSCTrecipients were analysised using NONMEM program respectively. The first orderconditional estimation with interaction （FOCE-I） was used on the model-buildingprocedure. The covariates including demographics, hematological indices, biochemicallevels, concurrent drugs and the genotypes of CYP3A4, CYP3A5and ABCB1SNPs wereevaluated quantitatively. In addition, the stability of the final model was validated by anonparametric bootstrap procedure.Results:（1） The frequencies of CYP3A4^*1G, CYP3A5*3, ABCB1C1236T, ABCB1G2677T/A and ABCB1C3435T SNPs were23%,81%,71%,44%/13%,43%and27.5%, 75%,68%,46%/14%,43%in Chinese paediatric aplastic anemia patients and allo-HSCTrecipients respectively. The frequencies of allele were72%,26%,71%,41%/17%,40%inChinese healthy subjects. There was no statistical difference among the three populationgroups.（2） Dose-adjusted C0（C0/D） was lower with TT genotype of ABCB1C1236T（25.71±10.66ng·ml-1per mg·kg-1） than those with ABCB11236C （31.73±13.82ng·ml-1per mg·kg-1）（p=0.043） in the paediatric aplastic anemia patients. And it was not beaffected by the other genotypes （p>0.05）. No significant differences in cyclosporine C0,dose and C0/D were observed between different genotypes of CYP3A4, CYP3A5andABCB1in allo-HSCT recipients （p>0.05）.（3） One-compartment model with first order absorption and elimination process wasthe best model for the data of94paediatric aplastic anemia patients. Apparent clearance（CL/F） and apparent volume of distribution （V/F） of cyclosporine were29.5L·h-1（standarderror [SE] of1.34） and419L （SE of52.2）. The interindividual variabilities of CL/F andV/F were27.8%and0.14%, respectively. The residual error was36.4%and70ng·ml-1.Age was identified as one significant covariate for CL/F. The validation showed that thefinal model was stable.（4）117patients were included and1571samples were collected in allo-HSCTrecipients. A one-compartment model with first absorption and elimination process bestdescribed the data. Clearance （CL） and volume of distribution （V） of cyclosporine were14.1L·h-1（SE of1.51） and980L （SE of244）. Bioavailability （F） was0.579（SE of0.0328）. The interindividual variabilities of CL, V, Ka and F were17.1%,57.5%,2.12%and31.1%, respectively. The residual error was29%and253ng·ml-1. The final modelshowed that post-operative week （POW）, inhibitor of cyclosporine （INHI）, hematocrit（HCT）, body weight （WT） and triglyceride （TG） were identified to be the main covariatesthat influenced CL of cyclosporine, and HCT had significant effect on V of cyclosporine.The inter-occasion variability （IOV） of CL, V and F were24.3%，80.6%and28%respectively. The internal validation showed that the final model was stable and accurate. （5） Significant difference was observed in graft-versus-host disease （GVHD） aftertransplantation between the subjects with the ABCB13435T and the ABCB13435CCcarriers in allo-HSCT recipients （p=0.012）.Conclusion:（1） Age was identified as one significant covariate for CL/F of paediatricaplastic anemia patients. Post-operative week （POW）, inhibitor of cyclosporine （INHI）,hematocrit （HCT）, body weight （WT） and triglyceride （TG） were identified to be the maincovariates that influenced CL of cyclosporine, and HCT had significant effect on V ofcyclosporine in the allo-HSCT recipients.（2） The study established the population pharmacokinetic models in Chinesepaediatric aplastic anemia patients and allo-HSCT recipients, respectively. The model ofcyclosporine identified the significant covariates in Chinese Patients with hematologicdiseases and would provide important information for clinical practice.（3） The allele of ABCB1C3435T may have relevance with the incidence of GVHD.