Estimation of Mycophenolic Acid Area Under the Curve With Limited-Sampling Strategy in Chinese Renal Transplant Recipients Receiving Enteric-Coated Mycophenolate Sodium

Background: The enteric-coated mycophenolate sodium (EC-MPS), whose active constituent is mycophenolic acid (MPA), has been widely clinically used for organ transplant recipients. However, its absorption is delayed due to its special designed dosage form, which results in difficulty to monitor the exposure of the MPA in patients receiving the EC-MPS. This study was aimed at developing a relatively practical and precise model with limited sampling strategy to estimate the 12-hour area under the concentration-time curve (AUC(0)-(12) (h)) of MPA for Chinese renal transplant recipients receiving EC-MPS. Methods: A total of 36 Chinese renal transplant recipients receiving the EC-MPS and tacrolimus were recruited in this study. The time point was 2 weeks after the transplantation for all the patients. The MPA concentrations were measured with enzymemultiplied immunoassay technique for 11 blood specimens collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after the morning dose of EC-MPS. The measured AUC was calculated with these 11 points of MPA concentrations with the linear trapezoidal rule. Limited sampling strategy was used to develop models for estimated AUC in the model group (n = 18). The bias and precision of different models were evaluated in the validation group (n = 18). Results: C-4 showed the strongest correlation with the measured AUC. The best 3 time point equation was 6.629 + 8.029 X C-0 + 0.592 X C-3 + 1.786 X C-4 (R-2 = 0.910; P < 0.001), whereas the best 4 time point equation was 3.132 + 5.337 X C-0 + 0.735 X C-3 + 1.783 X C-4 + 3.065 X C-8 (R-2 = 0.959; P < 0.001). When evaluated in the validation group, the 4 time point model had a much better performance than the 3 time point model: for the 4 time point model: R-2 = 0.873, bias = 0.505 [95% confidence interval (CI), -10.159 to 11.170], precision = 13.370 (95% CI, 5.186-21.555), and 77.8% of estimated AUCs was within 85%-115% of the measured AUCs; for the 3 time point model: R-2 = 0.573, bias = 6.196 (95% CI, -10.627 to 23.018), precision = 21.286 (95% CI, 8.079-34.492), and 50.0% of estimated AUCs was within 85%-115% of the measured AUCs. Conclusions: It demanded at least 4 time points to develop a relatively reliable model to estimate the exposure of MPA in renal transplant recipients receiving the EC-MPS. The long time span needed restricted its application, especially for the outpatients, but it could be a useful tool to guide the personalized prescription for the inpatients.