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

Abstract

Significant relationships between the mycophenolic acid (MPA) area under the concentration-time curve (AUC(0-12h)) 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. 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 (r(2) = 0.341-0.862) to a randomly selected subset of the profiles using linear regression and were used to estimate AUC(0-12h) for the profiles not included in the regression fit, comparing those estimates with the corresponding AUC(0-12h) 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. The model using c(0h), c(0.5h), and c(2h) was superior to all other models tested (r(2) = 0.862), minimizing prediction error for the AUC(0-12h) 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 + 6.49c(0h) + 0.76c(0.5h) + 2.43c(2h). 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 AUC(0-12h) calculated using all 12 concentrations. This limited sampling strategy provides an effective approach for estimation of the full MPA AUC(0-12h) in renal transplant patients receiving concomitant tacrolimus therapy.