Early Phase Limited Sampling Strategy Characterizing Tacrolimus and Mycophenolic Acid Pharmacokinetics Adapted to the Maintenance Phase of Renal Transplant Patients


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Abstract

The aim of this study was to examine whether a limited sampling strategy (LSS) to allow the simultaneous estimation of the area under the concentration-time curves (AUCs) of tacrolimus and mycophenolic acid (MPA) calculated in the early stage after renal transplantation could be applied to maintenance phase pharmacokinetics. Seventy Japanese patients were enrolled. One year after transplantation, samples were collected just before and 1, 2, 3, 4, 6, 9, and 12 hours after tacrolimus and mycophenolate mofetil administration at 9:00 am and at 9:00 pm. The prediction formulas on day 28 (tacrolimus AUC0-12 = 7.04·C0h + 1.71·C2h + 3.23·C4h + 15.19 and 2.25·C2h + 1.92·C4h + 7.27·C9h + 6.61, and MPA AUC0-12 = 0.26·C0h + 2.06·C2h + 3.82·C4h + 20.38 and 1.77·C2h + 2.34·C4h + 4.76·C9h + 15.94) were applied to pharmacokinetic data obtained at 1 year. Three error indices [percent mean prediction error (ME), % mean absolute error, and percent root mean squared prediction error (RMSE)] were used to evaluate the predictive bias, accuracy, and precision. The predicted AUC0-12 of tacrolimus and MPA at 3 time points, C2h-C4h-C9h, showed higher correlation with the measured AUC0-12 of tacrolimus and MPA (r2 = 0.817 and 0.789, respectively) in comparison with those at C0h-C2h-C4h. The values for the prediction formulas for tacrolimus AUC at 1 year using the C2h-C4h-C9h combination yielded less than 5% for %ME and 15% for %RMSE. The %ME and %RMSE values of the prediction formulas for tacrolimus AUC using the C0h-C2h-C4h combination were 6.3% and 15.9%, respectively. The %ME and %RMSE values of the prediction formulas for MPA AUC at 1 year using the C0h-C2h-C4h combination were 5.9% and 25.8%, respectively, and those for the C2h-C4h-C9h combination were 4.9% and 21.2%, respectively. AUC6-12/AUC0-12 of MPA 1 year after transplantation was significantly lower than 28 days after transplantation. An LSS using C2h-C4h-C9h seems to be applicable for predicting the AUC of tacrolimus and MPA at either posttransplantation stage. The enterohepatic circulation of MPA was significantly reduced 1 year after transplantation. Therefore, 1 year after transplantation, the estimation of the AUC0-12 of MPA for the C0h-C2h-C4h equations was imprecise. It is important that the LSS includes C9h because it contains information on the secondary plasma peak of MPA.

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