Population Pharmacokinetics Of Cyclosporine A In Patients With Renal Transplantation And Allogeneic Hematopoietic Stem Cell Transplantation And Its Application In Clinical Practice

Cyclosporine A (CsA), an effective immunosuppressant containing 11 amino acid residues, which was extracted from metabolite production of fungus, has been widely used to prevent and treat immunological rejection reaction in patients who have received solid organ transplantation and bone marrow transplantation. It greatly increases the successful ratio of graft and survival of patients. However, CsA is characterized by the narrow therapeutic window, larger interindividual and intraindividual variability of pharmacokinetic process and relatively serious adverse reactions. Therefore, individualized medication according to the different individual condition is desired.To design the individualized medication regimen, we need to know the individual pharmacokinetic parameters. The classical pharmacokinetic approach requires collecting multiple blood samples from one patient, which obviously increases the patient's suffering. So it is unfavorable in clinical practice. The population pharmacokinetic (PPK) method which was on the basis of combination of the classic pharmacokinetics model with statistic model uses the principle of extended least square algorithm to estimate the population pharmacokinetic parameters in one step by using the sparse plasma concentration data of patients and concurrently to test the effects of the various factors on pharmacokinetics parameters quantitatively. It can be used in clinical individualized medication.So far, the PPK studies of CsA have been mainly performed in the patients who received solid organs transplantion such as kidney, heart and liver transplantation and the patients with nephrotic syndrome. There was only one foreign paper reported the PPK study of CsA in allo-HSCT patients. From the results of all the studies, we could find that the results were different because of the the differences of diseases, races, populations and so on. Therefore, this paper was set to establish population pharmacokinetic models of CsA using the NONMEM method by the concentration data from the patients with renal transplantation and allogeneic hematopoietic stem cell transplantation in the general hospital of Air Force and investigate the influences of fixed effect factors such as weight, age, gender, hematological index, hepatic and renal function and coadministration on the pharmacokinetics parameters. The information obtained from this study is expected to offer reference for individual medication of CsA in clinical practice.This paper had the following two parts:1. Analysis of Correlation Factors Influencing Blood Concentration of CsA and Population Pharmacokinetics Study of CsA in Renal Transplantation Patients160 blood concentrations of CsA and clinical information data such as gander, age, body weight, the dosage of CsA, the corresponding biochemical testing values and coadministration were retrospectively collected from 62 renal transplantation patients. The data was analyzed with multiple linear regression method by using SAS 6.04 software to investigate the factors influencing the concentrations of CsA. The results showed that significant linear relationship was found between unit dose blood concentration of CsA and total bilirubin, the medication time and age (P< 0.05). Furtherly, a population pharmacokinetics model was set up by using the NONMEM method. The influences of covariate effects on parameters of PPK were estimated. The results showed that body weight (WT), haematocrit (HCT) and total bilirubin (TBIL) markedly affected the clearance rate of CsA. The final model formula is:CL/F=29.6×[1+0.0104×(WT-60.96)]×[1-1.16×(HCT-0.291)]×[1-0.0132 x (TBIL-10.84)] (L/h), V/F=3.85×WT (L), Ka=1.28 (h-1) (fixed). The interindividual variability (CV) for CL/F was 10.9%. The reliability and stability of the PPK model were confirmed by nonparametric bootstrap procedure, which indicated this model can offer reference for the rational use of CsA in clinical practice.2. Population Pharmacokinetics of CsA in Allogeneic Hematopoietic Stem Cell Transplantation Patients and Its Clinical Application281 trough plasma concentrations of CsA and covariates such as demographics, clinical laboratory values and coadministration were retrospectively collected from 73 allo-HSCT patients. Population modeling was performed using the NONMEM program. The results showed that the hematocrit (HCT), plasma albumin (ALB) level and coadministration of itraconazole (ITR) were found to significantly affect the clearance of CsA. The final model formula was:CL=28.2×[1-0.0263×(HCT-26.62)]×[1-0.0289×(ALB-37.63)]×[1-0.146×ITR](L/h);V=1080 (L);Ka=1.28 (h-1) (fixed);F=0.711. The interindividual variability for CL, V and F were 21.4%, 41.5% and 6.07%, respectively. The PPK model was validated to be effective and stable by bootstrap method. Clinical applications showed that the percent of difference between the predicted concentrations estimated by the final model and the observed were 2.6%～22.46%, and there was a good linear correlation between the predicted concentrations and the observed, which indicated that the PPK final model can be applied in clinical practice.