Population pharmacokinetic study of tacrolimus in patients with hematopoietic stem cell transplant

The present study is to establish the population pharmacokinetic (PPK) model of tacrolimus   and to estimate PPK parameters of tacrolimus for the individualization of tacrolimus administration in patients with hematopoietic stem cell transplant.  A total of 671 blood samples were collected from 68 hematopoietic stem cell transplant patients and clinical data were retrospectively collected from the medical records of these  patients.  Population pharmacokinetical analysis was performed using the nonlinear mixed-effect model (NONMEM) program.  The Bootstrap and data splitting were used simultaneously to validate the final population pharmacokinetical models.  The basic structural model was best described as one-compartment pharmacokinetical model with first-order absorption and elimination.  A number of covariates including demographic characteristic, biochemical and hematological index, combined drugs, inter-occasion variability (IOV) and other variables, e.g. primary disease, post operation days (POD), the type of transplantation and the sources of donor, were screened for their influence on the pharmacokinetic parameters of tacrolimus.  The population typical values of      tacrolimus CL, V, F were 12.1 L·h⁻¹, 686 L, 42.2%; and the inter-individual variability of these parameters were 23.5%, 96.4%, 43.8%, respectively.  The absorption rate constant was fixed 4.3 h⁻¹.  The residual error     between observed and model- predicted concentration was 3.03 ng·mL⁻¹.  The CYP enzyme inhibitor (INHI), POD and age were identified to be the main covariates that influence tacrolimus CL, and hemoglobulin (HGB) was the main covariate that may explain the variability in tacrolimus V.  The IOV of CL, V, F were 22.2%, 6.23%, 30.3%, respectively.  The population pharmacokinetic data obtained in the present study have significant clinical value for the individualization of tacrolimus therapy in hematopoietic stem cell transplant patients.