Inter-individual variability of Tacrolimus clearance in the early post-kidney transplantation: A model based population pharmacokinetic-pharmacogenetic analysis using estimated Ka from dense sampling data

Purpose: This study was designed to estimate the population pharmacokinetics and pharmacogenetics of tacrolimus in adult kidney transplantation recipients using dense sampling data and to evaluate the influence of clinical covariates including hemoglobin, hematocrit, platelet, post-operative days, concomitant immunosuppressant, CYP3A5 and ABCB1 polymorphisms.

Methods: We densely sampled at just before, 0.5, 1, 2, 4, 6, 12hr after administration of tacrolimus during after 10 to 15 post-operative days and trough levels until 6 months after transplantation. Clinical and genetic data were included for 6 months as well to evaluate covariates for pharmacokinetics of tacrolimus. Model development was conducted using NONMEM version 6 and model validation was done with Bootstrap and Visual Prediction Check.

Results: In model estimation, data of sixty-one Korean adult kidney transplant recipients taking tacrolimus were used for analysis. The estimated population mean values of clearance (CL/F) and volume of distribution (V/F) were 7.85L/h (RSE 56%) and 125L (RSE 26%), respectively. Absorption rate was estimated to 4.8 h^-1 (RSE 9%) and the lag time was fixed to 15 min. Concomitant steroid dose, post-operative days, hemoglobin, hematocrit and CYP3A5 genotype were identified as the covariates of CL/F. Age was the only factor affecting V/F significantly.

Conclusion: Our study identified significant factors affecting variability of tacrolimus pharmacokinetics in Korean kidney transplant recipients using dense sampling. This model will help to predict ideal dosage of tacrolimus more properly and develop rational guidelines for individual drug therapy after kidney transplantation.