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

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 AUC_0-12 = 7.04·C_0h + 1.71·C_2h + 3.23·C_4h + 15.19 and 2.25·C_2h + 1.92·C_4h + 7.27·C_9h + 6.61, and MPA AUC_0-12 = 0.26·C_0h + 2.06·C_2h + 3.82·C_4h + 20.38 and 1.77·C_2h + 2.34·C_4h + 4.76·C_9h + 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 AUC_0-12 of tacrolimus and MPA at 3 time points, C_2h-C_4h-C_9h, showed higher correlation with the measured AUC_0-12 of tacrolimus and MPA (r² = 0.817 and 0.789, respectively) in comparison with those at C_0h-C_2h-C_4h. The values for the prediction formulas for tacrolimus AUC at 1 year using the C_2h-C_4h-C_9h 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 C_0h-C_2h-C_4h 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 C_0h-C_2h-C_4h combination were 5.9% and 25.8%, respectively, and those for the C_2h-C_4h-C_9h combination were 4.9% and 21.2%, respectively. AUC_6-12/AUC_0-12 of MPA 1 year after transplantation was significantly lower than 28 days after transplantation. An LSS using C_2h-C_4h-C_9h 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 AUC_0-12 of MPA for the C_0h-C_2h-C_4h equations was imprecise. It is important that the LSS includes C_9h because it contains information on the secondary plasma peak of MPA.