Population Pharmacokinetics and Individualized Dosage Prediction of Cyclosporine in Allogeneic Hematopoietic Stem Cell Transplant Patients

Abstract Background Cyclosporine (CsA), a potent immunosuppressive agent used to prevent rejection, is characterized by large individual variability. The purpose of this study was to explore the pharmacokinetic characteristics of CsA and establish a CsA population pharmacokinetic model that could be used for personalized therapy in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients. Methods Clinical data were obtained from 117 allo-HSCT patients. The data analysis was performed using NONMEM software. A first-order conditional estimation with interaction (FOCE-I) method within NONMEM was used to estimate the parameters. The covariates, including demographics, hematological indices, biochemical levels, concurrent drugs, and genetic polymorphisms of CYP3A4 , CYP3A5 , and ABCB1 , were evaluated quantitatively. The stability of the final model was validated by a nonparametric bootstrap procedure. Results A total of 1,571 observed concentrations were collected. A 1-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of CsA. The typical values for clearance (CL), volume of distribution (V), and bioavailability were 29.6 L/hr, 605 L, and 0.619, respectively. The interindividual variability of these parameters was 20.4, 66.1, and 30.4%, respectively. The residual error was 31.4% and 23.7 ng/mL. The duration of CsA therapy, hematocrit, antifungal agent administration, triglycerides, and weight were identified as the main covariates that influenced CL, and hematocrit had a significant effect on V. The internal validation showed that the final model was stable and accurate. Conclusions This study established a population pharmacokinetic model of CsA in allo-HSCT patients that could provide the foundation for personalized use of CsA in the clinic.