Population pharmacokinetics of tacrolimus in adult kidney transplant recipients

Objectives: The aims of this study were to investigate the population pharmacokinetics of tacrolimus in adult kidney transplant recipients and to identify factors that explain variability. Methods: Population analysis was performed on retrospective data from 70 patients who received oral tacrolimus twice daily. Morning blood trough concentrations were measured by liquid chromatography-tandem mass spectrometry. Maximum likelihood estimates were sought for apparent clearance (CL/F) and apparent volume of distribution (V/F), with the use of NONMEM (GloboMax LLC, Hanover, Md). Factors screened for influence on these parameters were weight, age, gender, postoperative day, days of tacrolimus therapy, liver function tests, creatinine clearance, hematocrit fraction, corticosteroid dose, and potential interacting drugs. Results. CL/F was greater in patients with abnormally low hematocrit fraction (data from 21 patients only), and it decreased with increasing days of therapy and AST concentrations (P<.01). Average parameter estimates were as follows: CL/F=31.8 L/h (hematocrit<0.33), CL/F=24.2 L/h (hernatocrit>0.33), and V/F=2080 L. Marked interindividual variability (42% to 111%) and residual random error (3.7 ng/mL) were observed. On the basis of the derived model, a patient with normal AST (20 U/L) or high AST (200 U/L) concentrations 7 days after commencement of therapy would require a tacrolimus dose of 4.6 mg or 4.0 mg, respectively, to achieve a steady-state trough concentration of 10 ng/mL. Conclusions: The population pharmacokinetics of tacrolimus in adult kidney transplant recipients showed wide variability. Thus it is not possible to use a standard tacrolimus dose as an empiric predictor of concentration in this population. An understanding of factors that influence the pharmacokinetics of tacrolimus may assist in drug dosage decisions.