Therapeutic drug monitoring · 2025
Population Pharmacokinetic/Pharmacodynamic Model of the Impact of Cumulative Tacrolimus Exposure on Kidney Function After Liver Transplant.
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Tang Ningjia, Maeda Shinichirou, Okuda Masahiro
Аннотация
BACKGROUND: Tacrolimus-induced nephrotoxicity is a common adverse effect after liver transplantation. In this study, we aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate the relationships among tacrolimus dose, instantaneous and cumulative exposure, and kidney injury.
METHODS: Data from adult liver transplant recipients with a once-daily tacrolimus formulation were retrospectively analyzed. A sequential population PK/PD modeling approach using nonlinear mixed-effects modeling was applied. Exposure metrics included trough concentrations, the area under the concentration-time curve [area under the curve (AUC)] over a 24-hour (AUC 0-24h ) period, and cumulative AUC (cAUC) over 1-6 months. Renal function was defined as the change in estimated glomerular filtration rate (eGFR). Demographics, biochemical parameters, and concomitant medications were evaluated as covariates.
RESULTS: Tacrolimus trough concentrations and eGFR measurements were obtained from a total of 44 patients for 3360 and 3504 measurements, respectively. Tacrolimus PK was best described by a one-compartment model with additive interindividual variability. Clearance was influenced by hematocrit (HCT) and postoperative days (PODs) within the first 14 days. Among exposure metrics, only cAUC over 3 months was significantly associated with renal function decline and provided the best model fit. The final PK/PD model was a direct linear model, with baseline eGFR identified as a covariate on the slope, reflecting individual susceptibility to tacrolimus-associated renal changes.
CONCLUSIONS: Cumulative tacrolimus exposure over 3 months is a key determinant of nephrotoxicity and a valuable predictor for dose individualization. Our findings suggest that early PODs, HCT, and baseline renal function should be considered when optimizing tacrolimus therapy.
METHODS: Data from adult liver transplant recipients with a once-daily tacrolimus formulation were retrospectively analyzed. A sequential population PK/PD modeling approach using nonlinear mixed-effects modeling was applied. Exposure metrics included trough concentrations, the area under the concentration-time curve [area under the curve (AUC)] over a 24-hour (AUC 0-24h ) period, and cumulative AUC (cAUC) over 1-6 months. Renal function was defined as the change in estimated glomerular filtration rate (eGFR). Demographics, biochemical parameters, and concomitant medications were evaluated as covariates.
RESULTS: Tacrolimus trough concentrations and eGFR measurements were obtained from a total of 44 patients for 3360 and 3504 measurements, respectively. Tacrolimus PK was best described by a one-compartment model with additive interindividual variability. Clearance was influenced by hematocrit (HCT) and postoperative days (PODs) within the first 14 days. Among exposure metrics, only cAUC over 3 months was significantly associated with renal function decline and provided the best model fit. The final PK/PD model was a direct linear model, with baseline eGFR identified as a covariate on the slope, reflecting individual susceptibility to tacrolimus-associated renal changes.
CONCLUSIONS: Cumulative tacrolimus exposure over 3 months is a key determinant of nephrotoxicity and a valuable predictor for dose individualization. Our findings suggest that early PODs, HCT, and baseline renal function should be considered when optimizing tacrolimus therapy.