Prediction tacrolimus blood levels based on the Bayesian method in adult kidney transplant patients

Abstract

The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. We have previously described a tacrolimus population pharmacokinetics model obtained in an adult kidney transplant cohort. The aims of the present study were (1) to validate that model using an external dataset and (2) to evaluate the prediction using a Bayesian method. Data were retrospectively collected from 34 adult patients receiving kidney transplantation. Trough blood concentrations of tacrolimus were predicted using the empirical Bayesian method with sparse samples obtained during the previous week. The system performance was evaluated by the mean prediction error (ME), mean absolute prediction error (MAE). and root mean square error (RMSE). Patients were administrated oral or intravenous tacrolimus as part of a triple immunosuppressive regimen with mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity and by routine therapeutic drug monitoring. In our previous model, clearance increased with post transplantation days and with prednisone dosage. Concentrations predicted by the population mean pharmacokinetic parameter values match well with observed concentrations during oral therapy. Bayesian prediction using trough concentrations obtained after 21 days of treatment significantly decreased ME, MAE, and RMSE compared with predictions from data including this period. After 21 days of treatment, there was an insignificant bias ME (0.22 ± 2.59 ng/ml), a reasonable precision MAE (1.97 ± 1.69 ng/ml) and RMSE (1.28 ± 0.58 ng/ml). The present study demonstrates the suitability of the Bayesian method for the prediction of trough blood concentrations of tacrolimus using only few samples in adult kidney transplantation recipients.

Dosing equation for tacrolimus using genetic variants and clinical factors

“…Days post transplant was the most significant clinical factor affecting tacrolimus CL/F and has been previously shown to be associated with CL/F [9,10,[25][26][27].Tacrolimus CL/F decreased by 14% in days 6-10 post transplant and by 29% in days 11-180 post transplant, relative to the immediate post-transplant period (days 3-5). This decrease in CL/F is consistent with previous findings [10,26].…”

“…Various studies have demonstrated an induction of CYP3A enzymes by corticosteroid therapy [42][43][44]. Although controversial, studies have identified corticosteroid therapy as a significant factor towards tacrolimus CL/F [9,27,[45][46][47]. Clinical practice varies substantially between centres.Therefore, the attribution of the …”

Improved prediction of tacrolimus concentrations early after kidney transplantation using theory‐based pharmacokinetic modelling

“… proposed a model for initial dosing that was found to be imprecise during external evaluation . Models externally evaluated for Bayesian dose adjustments have been found imprecise in the first weeks post‐transplant . Six of the available models were evaluated for their ability to predict the tacrolimus area under the concentration–time curve in independent patients and were found unacceptably imprecise unless at least two individual concentrations within the dosing interval were known .…”

Pharmacokinetics and pharmacodynamics of tacrolimus in liver transplant recipients: inside the white blood cells

“…Therapeutic drug monitoring (TDM) based on TAC whole blood concentration assessment is commonly used as a marker to prevent ACR. Besides, a pharmacogenetic approach [4] or a dose individualization based on Bayesian models [5,6] or bottom-up approach [7] may be helpful to further optimize the individualization of TAC dosing in liver transplant recipients. However, it is still uncertain whether these two latter approaches have a significant impact on clinical outcome [8,9].…”