Abstract

Limited sampling strategies (LSS) for estimating the area under the concentration-time curve (AUC) of mycophenolic acid (MPA) in renal transplant children receiving concomitant tacrolimus have been developed, but they have not yet undergone full validation. The objectives of the present study were to evaluate the predictive performance of previously published LSS of MPA in an independent pediatric population and to validate a reliable and clinically applicable LSS for routine clinical practice. Published MPA LSS in renal transplant children were screened from the literature, and MPA predicted AUCs were calculated using these LSS. These predicted AUCs were then compared with the reference AUCs, which were calculated by the trapezoidal rule. External validation was prospectively performed in an independent validation group consisting of 44 renal transplant children. This group had a mean age of 12 years (range 3.45 - 20.57) and a mean weight of 35.8 kg (range 15.5 - 77.5). In this external validation dataset, the LSS2 equation: MPA-AUC0-12 = 12.6 + 7.78.C0 + 0.9.C1 + 1.3.C2 demonstrated good predictive performance. The correlation between the predicted and reference AUC using the LSS2 equation was r2= 0.88, with a percent error (PE) of 6.64, a root mean square error (RMSE) of 9.63, and a Bland-Altman bias of -1.36. The mean MPA-AUC0-12h values obtained from the LSS1 equation (MPA-AUC0-12 = 10.0 + 3.95×C0 + 3.24×C0.5 + 1.01×C2) and LSS2 were 65.23±33.84 µg.h/ml, 50.24±19.41 µg.h/ml, and 51.75±19.41 µg.h/ml, respectively. The correlation (r2) between full MPA-AUC0-12h and LSS2 (r2 = 0.88) was higher than that with LSS1 (r2 = 0.69). The linear regression value was superior with LSS2 (R2 = 0.77) compared to LSS1 (R2 = 0.472). Additionally, the RMSE was lower for the David Netto method (DNm; RMSE = 9.63) than for LSS1 (RMSE = 28.82). The Bland-Altman plot showed a bias of -1.36 for LSS2 and -14.99 for LSS1. These results indicate that a reliable and clinically applicable LSS was validated to predict the mycophenolic acid (mycophenolate mofetil [MFF]) AUC in renal transplant children receiving concomitant tacrolimus. This LSS can be routinely used to adapt individual doses of MMF.

Key words: Limited sampling strategy, mycophenolate mofetil, renal transplantation, children, tacrolimus.