Development and Validation of Limited Sampling Strategies for the Estimation of Mycophenolic Acid Area Under the Curve in Adult Kidney and Liver Transplant Recipients Receiving Concomitant Enteric-Coated Mycophenolate Sodium and Tacrolimus

Background:Mycophenolic acid (MPA) is widely used in solid organ transplantation. MPA absorption from enteric-coated mycophenolate sodium (EC-MPS) is delayed, which results in a delayed enterohepatic recirculation and subsequently higher and more variable MPA 12-hour trough concentration and t(max) values. Therefore, MPA trough level monitoring cannot be used to monitor MPA exposure in patients who are given EC-MPS. The aim of the study was to develop and validate a limited sampling strategy (LSS) for accurate prediction of the 12-hour area under the concentration-time curve (AUC(0-12h)) for MPA in patients who receive concomitant EC-MPS and Tacrolimus (Prograf or Advagraf) within 196 months posttransplantation. According to our knowledge, the LSS for MPA AUC estimation using high-performance liquid chromatography to determine MPA concentrations in plasma samples of kidney and liver transplant patients receiving EC-MPS and Tacrolimus (Advagraf) has not been previously evaluated.Methods:Seventy-four renal and liver transplant patients receiving EC-MPS and concomitant tacrolimus (either Prograf or Advagraf) provided a total of 74 pharmacokinetic profiles. MPA concentrations were measured using a validated high-performance liquid chromatography method for 9 plasma samples collected at predose and at 0.5, 1, 2, 3, 4, 6, 9, and 12 hours after the morning dose of EC-MPS after an overnight fast. LSS were developed and validated by stepwise multiple regression analysis with the use of a 2-group method (test, n = 37; and validation, n = 37).Results:The 3 and 4 time point equations using C-1h, C-3h, C-9h and C-1h, C-2h, C-3h, C-6h, respectively, were found to be superior to all other models tested. When these LSS models were tested in the validation group, the results were acceptable [for 3 time points equation: r(2) = 0.824, percentage of prediction error: 6.32 25.75, 95% confidence interval (CI): -40.71 to 79.76; percentage of absolute prediction error: 27.45 +/- 29.89, 95% CI: 0.04-199.92, predictive performance, 71% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean +/- SD: -0.03 +/- 0.24; for 4 time points equation: r(2) = 0.898, percentage of prediction error: 3.32 +/- 18.26, 95% CI: -49.35 to 51.06; percentage of absolute prediction error: 14.05 +/- 11.89, 95% CI 0.13-49.86, percentage of predictive performance, 83% of estimated AUCs comprised within 85%-115% of the measured full MPA AUC, natural logarithmic residuals (ln) mean +/- SD: -0.01 +/- 0.19].Conclusions:LSS equations using concentrations at 1, 3, and 9 hours or 1, 2, 3, and 6 hours time points provided the most reliable and accurate estimations of the MPA AUC in stable renal and liver transplant recipients treated with EC-MPS and tacrolimus. Further studies on independent groups of patients are required to confirm clinical utility of the presented LSS models.