Population Pharmacokinetics Study of Tacrolimus in Chinese Hematopoietic Cell Transplant Patients.

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. The population pharmacokinetics (PPK) of tacrolimus have been reported in solid organ transplantation patients, but few investigation of tacrolimus PPK in hematopoietic cell transplant patients. Our study is to characterize the factors that influence tacrolimus population pharmacokinetics in Chinese hematopoietic cell transplant patients.

Sixty-eight patients undergoing hematopoietic cell transplant were enrolled. The database (671 data points) collected from the patients was analyzed by using the nonlinear mixed-effect model (NONMEM) program. Patients were administered oral or/and intravenous tacrolimus as part of immunosuppressive regimen that also included corticosteroids. And the robustness and accuracy of the model were assessed using bootstrap. A number of covariates including demographic characteristic, biochemical and hematological index, drug combination, IOV (inter-occasion variability) and other factors (e.g. Cause, POD, the type of transplantation and the sources of donor) were evaluated for their influence on the tacrolimus population pharmacokinetic parameters.

The basic model was selected a one-compartment pharmacokinetic model with first-order absorption and elimination. The typical values of tacrolimus CL, V, F were 12.1 L·h^-1, 686 L, 42.2%, respectively. And the inter-individual variations of CL, V, F 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 covariates that influenced the population pharmacokinetics parameters of tacrolimus included inhibitor (INHI), post operation days (POD), age and hemoglobulin (HGB) in the final regression model. The IOV of CL, V, F were 22.2%, 6.23%, 30.3%, respectively.

The covariates included INHI, POD, AGE, HGB and IOV would significantly influence tacrolimus population pharmacokinetics parameters in hematopoietic cell transplant patients.

No relevant conflicts of interest to declare.