Bootcongres

Background: The narrow therapeutic index and wide variability in pharmacokinetics of tacrolimus require therapeutic drug monitoring. Total exposure is reflected by the area under the concentration-time curve (AUC_0-24), calculated on the basis of a full pharmacokinetic profile. Limited sampling strategies to estimate the AUC have been developed for practical use in ambulatory patients. For the prolonged-release formulation of tacrolimus, which has to be taken only once a day, limited sampling strategies have not been reported.

Aim: To develop a limited sampling strategy for ambulatory patients to estimate the AUC_0-24 of prolonged-release tacrolimus.

Methods: 26 kidney recipients, at least 6 months after transplantation, receiving prolonged-release tacrolimus (Advagraf®) as part of their immunosuppressive regimen were enrolled. In each patient, seven blood samples were collected during a period of 24 hours after the intake of prolonged-release tacrolimus by use of the validated dried blood spot method. Tacrolimus levels were measured with HPLC-tandem mass spectrometry. Best subset selection multiple linear regression was performed to derive limited sampling equations predictive of the AUC_0-24. To assess the predictive performances of the models, residuals for each patient were calculated based on models fitted to a dataset where that patient was omitted. Potential bias in the predictions was assessed using the median percentage prediction error (MPPE). Imprecision was assessed using median absolute percentage prediction error (MAPE) and root median squared prediction error (RMSE). 

Results: All participants were of Caucasian ancestry. The median daily dose of prolonged-release tacrolimus was 4.0 mg (range 1.5-10.0). The geometric mean of the trough level was 6.2 µg/L (95% confidence interval 4.8-7.9). The prediction formula for the AUC_0-24 using the time points 0, 2, and 4 hours after ingestion (C_0h-C_2h-C_4h) gave the highest correlation with the AUC_0-24 (r² = 0.9567): 44.9 + 8.9 x C_0h + 2.1 x C_2h + 7.6 x C_4h. The MPPE, MAPE, and RMSE of the formula using C_0h-C_2h-C_4h were 0.38%, 4.80% and 11.13%, respectively. This was within the acceptable limits for accuracy of 5%, 10%, and 15%, respectively. For the same patients, the correlation between trough levels and AUC was lower (r² = 0.7779).

Conclusion: In the outpatient clinic, a limited sampling strategy using C_0h-C_2h-C_4h can be used for reliable estimation of the AUC_0-24 of prolonged-release tacrolimus.