Limited Sampling Strategy for the Estimation of Mycophenolic Acid Area under the Curve in Adult Renal Transplant Patients Treated with Concomitant Tacrolimus

Abstract

Background: Significant relationships between the mycophenolic acid (MPA) area under the concentration–time curve (AUC0–12h) and the risks for acute rejection and side effects have been reported. We developed a practical method for estimation of MPA AUCs. Regression equations were developed using repeated cross-validation for randomly chosen subsets, characterized statistically, and verified for acceptable performance. Methods: Twenty-one renal transplant patients receiving 0.5 or 1.0 g of mycophenolate mofetil twice daily and concomitant tacrolimus provided a total of 50 pharmacokinetic profiles. MPA concentrations were measured by a validated HPLC method in 12 plasma samples collected at predose and at 30 and 60 min; 2, 3, 4, 6, 8, 9, 10, 11, and 12 h; 1 and 2 weeks; and 3 months after transplantation. Twenty-six 1-, 2-, or 3-sample estimation models were fit (r2 = 0.341–0.862) to a randomly selected subset of the profiles using linear regression and were used to estimate AUC0–12h for the profiles not included in the regression fit, comparing those estimates with the corresponding AUC0–12h values, calculated with the linear trapezoidal rule, including all 12 timed MPA concentrations. The 3-sample models were constrained to include no samples past 2 h. Results: The model using c0h, c0.5h, and c2h was superior to all other models tested (r2 = 0.862), minimizing prediction error for the AUC0–12h values not included in the fit (i.e., the cross-validation error). The regression equation for AUC estimation that gave the best performance for this model was: 7.75 + 6.49c0h + 0.76c0.5h + 2.43c2h. When we applied this model to the full data set, 41 of the 50 (82%) estimated AUC values were within 15% of the value of AUC0–12h calculated using all 12 concentrations. Conclusions: This limited sampling strategy provides an effective approach for estimation of the full MPA AUC0–12h in renal transplant patients receiving concomitant tacrolimus therapy.

Long‐Term Changes in Mycophenolic Acid Exposure in Combination with Tacrolimus and Corticosteroids Are Dose Dependent and Not Reflected by Trough Plasma Concentration: A Prospective Study in 100 De Novo Renal Allograft Recipients

“…tween what is theoretically desired and practically feasible. Using three MPA sampling points at 0, 40 minutes, and 2 hours postdosing (C 0 , C 40 , C 2 ), an equation was derived that explained 78% of the variance of the full AUC (r 2 = 0.78, p < 0.0001), which is comparable with that noted by other authors 34 but inferior to that of Pawinski and coworkers, 35 who determined MPA plasma concentrations using HPLC rather than immunoassay.…”

Limited Sampling Strategy for Predicting Area Under the Concentration‐Time Curve of Mycophenolic Acid in Adult Lung Transplant Recipients

“…28 Due to the various challenges in acquiring limited sampling strategies, convenient and valid strategies for immunosuppressive agents are wanting. Although limited sampling strategies for estimation of mycophenolic acid AUC have been established recently by various groups (Table 4), 17,19,20,[29][30][31][32] most of the strategies were center specific, as suggested sampling times differed among research groups. This is probably due to the different sampling times used in the pharmacokinetic profiling and the varying number of samples, which ranged from 8-13 (Table 4).…”

“…Limited sampling strategies for mycophenolic acid have been suggested by several groups. [17][18][19][20][21][22][23] However, all these studies were conducted in the kidney transplant population, and some suggest sampling times that are not clinically convenient (e.g., beyond 2 hrs after drug administration). To our knowledge, no limited sampling strategy has been established for the lung transplant population, even though about 50% of the lung transplant population receives mycophenolate mofetil as part of their immunosuppressive therapy.…”

Higher exposure to mycophenolic acid with sirolimus than with cyclosporine cotreatment

“…Indeed, the MMF dose of 0.5 g twice daily was reported to lead to MPA concentrations within the therapeutic range in renal graft recipients cotreated with tacrolimus. 23 For practical reasons, the determination of MPA AUC is difficult because multiple blood samples collected at precise time points are needed. Because a poor correlation between MPA C 0 and MPA AUC was previously shown in cyclosporine-treated patients, limited sampling strategies were developed to estimate MPA AUC 0-12 with the use of a few blood samples collected during the absorption phase.…”