Validation of limited sampling strategy for estimation of mycophenolic acid exposure during the first year after heart transplantation.

BACKGROUND: Individualization of mycophenolate mofetil (MMF) dosing based on mycophenolic acid (MPA) therapeutic drug monitoring may minimize the risk of organ transplant rejection. The MPA area under the 12-hour concentration-time curve (MPA-AUC(0-12h)) is a more powerful predictor of rejection than are MPA trough levels. Measurement of MPA-AUC(0-12h,) however, is difficult and clinically impractical. The limited sampling strategy (LLS) has been proposed to overcome this problem. OBJECTIVE: To validate the predictive performance of MPA LSS algorithms previously published for heart transplant (HTx) recipients (initial group) when applied to a new independent group of 29 HTx recipients (validation group) during the first year after transplantation. PATIENTS AND METHODS: In a previous study, we established 2 algorithms using a LSS in HTx recipients: (1) 5.568 + 0.902 x C(1.25) + 2.022 x C(2) + 4.594 x C(6) and (2) 3.8 + 1.025 . C(1.25) + 1.819 x C(2) + 1.566 x C(4) + 3.479 x C(6). Agreement between abbreviated AUC and the full AUC(0-12h) was tested using the Bland-Altman method. The validation group was used to test and assess bias and precision. RESULTS: The 2 LSS algorithms used predicted the corresponding MPA-AUC(0-12h) with a mean bias of -4.85% and -3.6% and mean precision of 15.9% and 14%, respectively. CONCLUSIONS: The MPA-AUC(0-12h) obtained using the LSS may be useful to guide clinical management and dosing. This study prospectively validates 2 algorithms for calculation of MPA-AUC(0-12h) using an LSS calculated in HTx recipients. Bias and precision values suggest that our algorithms could be used for MPA therapeutic drug monitoring predictions in HTx recipients who share the same characteristics.

Therapeutic mycophenolic acid monitoring by means of limited sampling strategy in orthotopic heart transplant patients.

Therapeutic drug monitoring (TDM) is essential to maintain the efficacy of many immunosuppressant drugs while minimizing their toxicity. TDM of mycophenolate mofetil requires area under the curve AUC determinations but appears laborious, costly, and clinically impractical. To overcome these problems, limited sampling strategies (LSS) have been proposed in adult and pediatric renal transplant patients. The purpose of this study was to develop an LSS in heart transplant patients. Forty-four mycophenolic acid (MPA) full AUC(0-12h) profiles were generated by high-performance liquid chromatography in nine heart transplant patients during the first 12 weeks posttransplant. Each patient received concomitant cyclosporine and prednisone therapy. Multiple stepwise regression analysis was used to define the time points of MPA levels to explain the MPA AUC(0-12h). Agreement between abbreviated AUC and the full AUC(0-12h) was tested by means of a Bland and Altman analysis. The highest coefficient of determination r(2) among MPA AUC and single concentrations (r(2) = .610) was observed with C(2), while C(12) provided the lowest one (r(2) = .003). Stepwise linear regression showed that the minimal model with the best estimation of MPA AUC(0-12h) was obtained at timed values of 1.25, 2, and 6 hours. The corresponding estimated model was AUC = 5.568 + 0.902 * C(1.25) + 2.022 * C(2) + 4.594 * C(6) (r(2) = .926). Bland and Altman analysis revealed good agreement between predicted AUC and full AUC. A further interesting model equation obtained by four samples was AUC = 3.800 + 1.015 * C(1.25) + 1.819 * C(2) + 1.566 * C(4) + 3.479 * C(6) (r(2) = .948).