Population pharmacokinetics of cyclosporine A based on NONMEM in Chinese allogeneic hematopoietic stem cell transplantation recipients

To set up a population pharmacokinetic (PPK) model of cyclosporine A (CsA) in Chinese allogeneic hematopoietic stem cell transplantation (allo-HSCT) patients to provide reference for individualized medication in clinical practice. 281 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 general model of NONMEM expressed by differential equation. Hematocrit (HCT), plasma albumin (ALB) level, and coadministration of itraconazole (ITR) were found to significantly affect the clearance of CsA (CL, L/h). 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 = 1,080 (L); Ka = 1.28 (h−1); F = 0.711. The interindividual variabilities for CL, V and F were 21.4, 41.5 and 6.07 %, respectively. The residual error was 0.00422 mg/L. The PPK model was validated to be effective and stable by bootstrap method. Clinical applications showed there was a good linear correlation between the predicted concentrations and the observed (y = 1.0095x + 0.0082, r = 0.9309, p < 0.0001). The PPK final model of CsA in Chinese allo-HSCT patients can be established using the NONMEM program which can be applied in clinical allo-HSCT practice when characteristics of patients fit in with those of subpopulation in the study.