Analyses of AUC(0-12) and C0 Compliances within Therapeutic Ranges in Kidney Recipients Receiving Cyclosporine or Tacrolimus.

Aurelija Radzevičienė,Rima Maslauskienė,Edmundas Kaduševičius,Rūta Vaičiūnienė,Edgaras Stankevičius,Pierre Marquet

doi:10.3390/jcm9123903

Abstract

The AUC (area under the concentration time curve) is considered the pharmacokinetic exposure parameter best associated with clinical effects. Unfortunately, no prospective studies of clinical outcomes have been conducted in adult transplant recipients to investigate properly the potential benefits of AUC(0–12) monitoring compared to the C0-guided therapy. The aim of the present study was to compare two methods, C0 (through level) and AUC(0–12) (area under the concentration time curve), for assessing cyclosporine and tacrolimus concentrations. The study included 340 kidney recipients. The AUC(0–12) was estimated using a Bayesian estimator and a three-point limited sampling strategy. Therapeutic drug monitoring of tacrolimus performed by using AUC(0–12) and C0 showed that tacrolimus in most cases is overdosed when considering C0, while determination of the AUC(0–12) showed that tacrolimus is effectively dosed for 27.8–40.0% of patients receiving only tacrolimus and for 25.0–31.9% of patients receiving tacrolimus with MMF (mycophenolate mofetil). In the 1–5 years post-transplantation group, 10% higher CsA (cyclosporine) dose was observed, which was proportionate with a 10% higher AUC(0–12) exposure value. This indicates good compatibility of the dosage and the AUC(0–12) method. The Bland–Altman plot demonstrated that C0 and AUC(0–12) might be interchangeable methods, while the ROC (receiver operating characteristic) curve analysis of the C0/AUC(0–12) ratio in the tacrolimus-receiving patient group demonstrated reliable performance to predict IFTA (interstitial fibrosis and tubular atrophy) after kidney transplantation, with an ROC curve of 0.660 (95% confidence interval (CI): 0.576–0.736), p < 0.01. Moreover, AUC(0–12) and C0 of tacrolimus depend on concomitant medication and adjustment of the therapeutic range for AUC(0–12) might influence the results.

Highlights

Due to the narrow immunosuppressants’ therapeutic range, highly variable pharmacokinetics, inter-individual differences, and a tendency of interactions mainly occurring during the metabolism, which are cytochrome P450 3A4 (CYP3A4)-mediated therapeutic window and fairly common adverse effects [1,2], prescription of immunosuppressive medication requires continual follow-up of the drug blood concentration
The results of this study showed that attention should be drawn to the fact that the assessment of area under the concentration time curve (AUC)(0–12) exposure values was made using the standard therapeutic range
Therapeutic drug monitoring of tacrolimus performed by using AUC(0–12) and C0 showed that tacrolimus is in most cases overdosed when considering C0, while the determination of AUC(0–12) showed that tacrolimus is effectively dosed for 27.8–40.0% of the patients receiving only tacrolimus and for 25.0–31.9% of the patients receiving tacrolimus with MMF

Summary

Introduction

Due to the narrow immunosuppressants’ therapeutic range, highly variable pharmacokinetics, inter-individual differences, and a tendency of interactions mainly occurring during the metabolism, which are cytochrome P450 3A4 (CYP3A4)-mediated therapeutic window and fairly common adverse effects [1,2], prescription of immunosuppressive medication requires continual follow-up of the drug blood concentration. Short-term outcomes are better tailored versus the long-term ones despite implementation of various strategies into clinical practice. Pharmacogenetics, and other assays have been developed to guide tailoring of immunosuppression; promising results have been obtained, trials showing their ability to improve long-term outcomes are lacking and urgently needed [3]. The standard care guidelines after kidney transplantation involve pharmacokinetic monitoring. It is not standardized and can be performed using diverse techniques, as C0, C2, and the area under the concentration time curve (AUC). There were significant differences in C0, C2, and the calculated AUC after shifting to single daily dosing of cyclosporine [4] The AUC might be calculated in accordance to the trapezoidal rule, the Bayesian or other model and gauge different time points [5], different clinical covariates [6], which leads to inter-clinical and inter-laboratory variability [7]

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