A Population Pharmacokinetic Model and Dosing Algorithm to Guide the Tacrolimus Starting and Follow-Up Dose in Living and Deceased Donor Kidney Transplant Recipients

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INTRODUCTION: Tacrolimus treatment is complicated by its narrow therapeutic range and large inter- and intra-patient variability. This study aimed to develop a population pharmacokinetic model and dosing algorithm to predict an individual's dose requirement following living and deceased donor kidney transplantation. METHODS: In this international, multicenter, retrospective study, data was collected from patients who had received a living or a deceased donor kidney and received tacrolimus twice daily. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling (NONMEM). RESULTS: This study included 13,427 tacrolimus concentrations from 1180 kidney transplant recipients. A two-compartment model with first-order absorption best described the data. The mean absorption rate was 6.59/h, apparent clearance 20.7 L/h, central volume of distribution 705 L, and peripheral volume of distribution 7670 L. Higher age, creatinine, and hematocrit, as well as lower height, were associated with lower tacrolimus clearance. Tacrolimus clearance was higher for cytochrome P450 (CYP) 3A5*1 carriers compared with CYP3A5*3/*3 individuals, and lower for CYP3A4*22 carriers compared with CYP3A4*1/*1 patients. Together, these covariates explained 19.3% of the inter-individual variability in clearance. From the full model, a starting dose algorithm was developed with age, height, and the CYP3A4 and CYP3A5 genotypes as covariates. Both the full model and the starting dose algorithm were successfully internally validated. CONCLUSIONS: In this international, multicenter study, age, CYP3A4 and CYP3A5 genotype, creatinine, height, and hematocrit were identified as significant covariates associated with tacrolimus pharmacokinetics, and can be used to predict the optimal individual's dose requirement for both living and deceased donor kidney transplant recipients.

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