Usefulness of limited sampling strategy for mycophenolic acid area under the curve considering postoperative days in living-donor renal transplant recipients with concomitant prolonged-release tacrolimus

• Main Authors: Tomoyuki Enokiya, Kouhei Nishikawa, Yuichi Muraki, Takuya Iwamoto, Hideki Kanda, Yoshiki Sugimura, Masahiro Okuda
• Format: Article
• Language: English
• Published: BMC 2017-06-01
• Series: Journal of Pharmaceutical Health Care and Sciences
• Subjects: Mycophenolate mofetil; Limited sampling strategy; Living-donor renal transplantation; Mycophenolic acid; Therapeutic drug monitoring
• Online Access: http://link.springer.com/article/10.1186/s40780-017-0086-7
• ISSN: 2055-0294

Abstract Background The optimal dose of mycophenolate mofetil (MMF) in renal transplant patients has been recommended to be decided on the basis of area under the concentration-time curve (AUC0-12) of mycophenolic acid (MPA). Although meta-analysis has revealed that postoperative day (POD) is an influencing factor in MPA pharmacokinetics, there are no reports regarding a limited sampling strategy (LSS) for MPA AUC in consideration of POD. The aim of this study was to construct of an LSS considering POD that appropriately expresses the MPA AUC following renal transplantation and evaluation of the usefulness. Methods Serum concentration–time profiles (measured AUC0-12) comprising nine sampling points over 12 h were analyzed in 36 living-donor renal transplant recipients after MMF administration with concomitant once-daily prolonged-release tacrolimus. Two LSSs were developed by stepwise multiple regression analysis (Method A: not classified by PODs; Method B: classified by PODs into POD < 31 and POD ≥ 31). Each LSS comprised four blood-sampling points within 6 h after MMF administration. Precision and reliability were verified by using root-mean-square error (RMSE), correlation coefficient (R2), and coefficient of determination (q2) by using leave-one-out cross-validation. The absolute values of the difference between measured and estimated AUCs (delta AUC) were compared for both estimating equations. Results One-hundred samples obtained from 36 recipients for AUC0-12 comprised POD < 31 (n = 39) and POD ≥ 31 (n = 61). Estimation of AUC0-12 by Method B resulted in better accuracy and reliability (Method A: RMSE = 5.5, R2 = 0.85, q2 = 0.83; Method B: POD < 31: RMSE = 5.5, R2 = 0.86, q2 = 0.83; POD ≥ 31: RMSE = 3.9, R2 = 0.92, q2 = 0.89) and significantly lower median delta AUC compared with that by Method A (delta AUC: 2.6 (0.0–11.6) v.s. 3.9 (0.1–18.1), p = 0.032). Conclusion These results suggest that LSS, classified as POD < 31 or POD > 31, would provide more accurate and reliable estimation of MPA AUC0-12 in Japanese living-donor renal transplant patients.