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. © 2002 American Association for Clinical Chemistry.