Examining Whole Blood, Total and Free Plasma Tacrolimus in Elderly Kidney Transplant Recipients.

Background: Therapeutic monitoring is routinely performed to ensure tacrolimus whole-blood concentrations fall within a predefined target. Despite this, patients still experience inefficacy and toxicity that could be related to variability in free (unbound) tacrolimus exposure. Therefore, the aim of this study was to compare tacrolimus-free plasma (Cu), total plasma (Cp), and whole-blood (Cwb) concentrations in adult kidney transplant recipients and to characterize tacrolimus disposition across different matrices.

Methods: Twelve-hour concentration-time profiling was performed in 15 recipients, allowing simultaneous measurement of Cu, Cp, and Cwb. Pharmacokinetic parameters were estimated using noncompartmental analysis. The relationship between Cwb and Cp were examined using a capacity-limited binding model, incorporating the hematocrit fraction (fHCT) to estimate maximum binding concentration (Bmax) and dissociation constant (Kd). The relationship between Cp and Cu was evaluated using a linear binding model to estimate the nonspecific binding parameter (Nplasma). Nonlinear regression analysis was used to obtain estimates of Bmax, Kd, and Nplasma.

Results: A total of 195 paired Cwb, Cp, and Cu values were collected. The median ratios of Cwb:Cp, Cp:Cu, and Cwb:Cu were 9:1, 20:1, and 138:1, respectively. Variability in free plasma exposure was large; free trough values ranged from 8 to 51 ng/L and free area-under-the-concentration-time-curve values ranged from 424 to 7160 ng·h/L. Median (range) estimates of Bmax, Kd, and Nplasma were 90.4 µg/L (22.4-752.5 µg/L), 2.36 µg/L (0-69.2 µg/L), and 0.05 (0.035-0.085), respectively. The interindividual variability (CV%) in binding parameters was considerable (Bmax 117.2%; Nplasma 32.5%).

Conclusions: Large variability was observed in tacrolimus-free plasma exposure and binding parameters. Future research to characterize the relationship between tacrolimus Cu and patient outcomes may be of benefit.