Body composition is associated with tacrolimus pharmacokinetics in kidney transplant recipients

Abstract

Purpose A population pharmacokinetic (popPK) model may be used to improve tacrolimus dosing and minimize under- and overexposure in kidney transplant recipients. It is unknown how body composition parameters relate to tacrolimus pharmacokinetics and which parameter correlates best with tacrolimus exposure. The aims of this study were to investigate which body composition parameter has the best association with the pharmacokinetics of tacrolimus and to describe this relationship in a popPK model. Methods Body composition was assessed using bio-impedance spectroscopy (BIS). Pharmacokinetic analysis was performed using nonlinear mixed effects modeling (NONMEM). Lean tissue mass, adipose tissue mass, over-hydration, and phase angle were measured with BIS and then evaluated as covariates. The final popPK model was evaluated using goodness-of-fit plots, visual predictive checks, and a bootstrap analysis. Results In 46 kidney transplant recipients, 284 tacrolimus concentrations were measured. The base model without body composition parameters included age, plasma albumin, plasma creatinine, CYP3A4 and CYP3A5 genotypes, and hematocrit as covariates. After full forward inclusion and backward elimination, only the effect of the phase angle on clearance (dOFV = − 13.406; p < 0.01) was included in the final model. Phase angle was positively correlated with tacrolimus clearance. The inter-individual variability decreased from 41.7% in the base model to 34.2% in the final model. The model was successfully validated. Conclusion The phase angle is the bio-impedance spectroscopic parameter that correlates best with tacrolimus pharmacokinetics. Incorporation of the phase angle in a popPK model can improve the prediction of an individual’s tacrolimus dose requirement after transplantation.

Impact of obesity on the conversion of immediate‐release tacrolimus to extended‐release tacrolimus in kidney transplant recipients

“…One explanation for this is that body composition impacts tacrolimus distribution and thus overall exposure. 16 In support of this,…”

“…One explanation for this is that body composition impacts tacrolimus distribution and thus overall exposure 16 . In support of this, Francke and colleagues developed a model based on body composition parameters and suggested that body composition is predictive of tacrolimus dosing in kidney transplant recipients 16 . The investigators found that the strongest correlation for tacrolimus PK was the phase angle, which is related to cellular membrane integrity and permeability, hydration and body cell mass; which can be influenced by body composition 16 …”

“…16 The investigators found that the strongest correlation for tacrolimus PK was the phase angle, which is related to cellular membrane integrity and permeability, hydration and body cell mass; which can be influenced by body composition. 16 In our study, obese patients had a significantly lower TITR. There are several hypotheses that may help explain this finding.…”

“…Our findings are consistent with these previous analyses and demonstrate that utilizing AdjBW may lead to more accurate mg/kg dosing in both IR and LCP tac formulations. One explanation for this is that body composition impacts tacrolimus distribution and thus overall exposure 16 . In support of this, Francke and colleagues developed a model based on body composition parameters and suggested that body composition is predictive of tacrolimus dosing in kidney transplant recipients 16 .…”

Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study

“…None of the body size indicators contributed to variability, which may be explained by the fact that the formulas that were used to estimate these were not specifically developed for pregnancy. A previous study did find a correlation between bioimpedance spectroscopy‐derived phase angle, calculated as the arc tangent of reactance over resistance, and tacrolimus CL/F 36 . Possibly, despite the absence of a correlation with the estimated values, there may be a correlation when measuring body composition in pregnant kidney transplant recipients, which could explain a part of the changes in tacrolimus CL/F, considering the significant alterations in body composition that occur during pregnancy.…”