The aim of this study was to develop a limited sampling strategy to allow the simultaneous estimation of the area under the concentration-time curves (AUCs) of tacrolimus and mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil, using a small number of samples from patients undergoing renal transplantation. Fifty Japanese patients were enrolled. On day 28 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 9:00 pm. The full pharmacokinetic profiles obtained from these timed concentration data were used to choose the best sampling times. Three error indices (percent mean error, percent mean absolute error, and percent relative mean square error) were used to evaluate the predictive bias, accuracy, and precision. The predicted AUC0-12 of MPA calculated at the three time points of C2h-C4h-C9h best approximated the actual AUC0-12 of MPA (r = 0.877), and the AUC0-12 of tacrolimus calculated at the same time points predicted a good correlation with the actual AUC (r = 0.928). When the three sampling times of trough level (C0h) and two other points within 4 hours after administration were used, the three points of C0h-C2h-C4h were the best points for estimation of the AUC0-12 tacrolimus and MPA (AUC0-12 = 7.04.C0 + 1.71.C2 + 3.23.C4 + 15.19, r = 0.799, P < 0.001 and AUC0-12 = 0.26.C0 + 2.06.C2 + 3.82.C4 + 20.38, r = 0.693, P < 0.001, respectively). The percent mean error, percent mean absolute error, and percent relative mean square error of the prediction formula using the three time points of C0h-C2h-C4h were -0.3%, 8.8%, and 13.5% for tacrolimus and 2.9%, 17.1%, and 21.5% for MPA, respectively. A limited sampling strategy using C2h-C4h-C9h provides the most reliable and accurate simultaneous estimation of the AUC0-12 of tacrolimus and MPA in patients undergoing renal transplantation. In addition, a limited sampling strategy using C0h-C2h-C4h is recommended for the simultaneous estimation of the AUC0-12 of tacrolimus and MPA when focused on samples collected within 4 hours after administration for clinical expediency.

No abstract

C0-guided monitoring may lead to similar AUC0-24 values for both formulations. However, to maintain the same AUC0-24 value, a higher dose of Tac-QD than Tac-BID may be needed, especially for CYP3A5 expressers, in the early stage posttransplantation. The narrow interindividual variability of Tac-QD pharmacokinetics and its difference between CYP3A5 expressers and nonexpressers might contribute to a dosing strategy based on CYP3A5 genotype.

It is possible to comprehensively evaluate CYP2C19 activity using the actual measured value of the VRCZ/N-oxide ratio in patients taking VRCZ. The predictive performance of the VRCZ/N-oxide ratio was improved by including the route of administration, C-reactive protein level, and patient age in addition to the CYP2C19 genotype as predictive factors.

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 x C 0h + 1.71 x C 2h + 3.23 x C 4h + 15.19 and 2.25 x C 2h + 1.92 x C 4h + 7.27 x C 9h + 6.61, and MPA AUC 0-12 = 0.26 x C 0h + 2.06 x C 2h + 3.82 x C 4h + 20.38 and 1.77 x C 2h + 2.34 x C 4h + 4.76 x 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.