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

¹ Department of Pathology & Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104.

² GlaxoSmithKline, Research Triangle Park, NC 27709.

³ Fujisawa Healthcare, Inc., Deerfield, IL 60015.

^aAddress correspondence to this author at: Department of Pathology & Laboratory Medicine, 7 Founders Pavilion, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104. Fax 215-662-7529; e-mail shawlmj{at}mail.med.upenn.edu.

Background: 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.

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 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.

Results: The model using c_0h, c_0.5h, and c_2h was superior to all other models tested (r² = 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.

Conclusions: 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.

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