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Limited Sampling Strategy for Simultaneous Estimation of the Area Under the Concentration-Time Curve of Tacrolimus and Mycophenolic Acid in Adult Renal Transplant Recipients

Miura, Masatomo PhD*; Satoh, Shigeru MD, PhD; Niioka, Takenori PhD; Kagaya, Hideaki PhD*; Saito, Mitsuru MD; Hayakari, Makoto PhD; Habuchi, Tomonori MD, PhD; Suzuki, Toshio PhD*

doi: 10.1097/FTD.0b013e31815f5416
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The aim of this study was to develop a limited sampling strategy to allow the simultaneous estimation of the area under the concentration-time curves (AUCs) of tacrolimus and mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil, using a small number of samples from patients undergoing renal transplantation. Fifty Japanese patients were enrolled. On day 28 after transplantation, samples were collected just before and 1, 2, 3, 4, 6, 9, and 12 hours after tacrolimus and mycophenolate mofetil administration at 9:00 am and 9:00 pm. The full pharmacokinetic profiles obtained from these timed concentration data were used to choose the best sampling times. Three error indices (percent mean error, percent mean absolute error, and percent relative mean square error) were used to evaluate the predictive bias, accuracy, and precision. The predicted AUC0-12 of MPA calculated at the three time points of C2h-C4h-C9h best approximated the actual AUC0-12 of MPA (r2 = 0.877), and the AUC0-12 of tacrolimus calculated at the same time points predicted a good correlation with the actual AUC (r2 = 0.928). When the three sampling times of trough level (C0h) and two other points within 4 hours after administration were used, the three points of C0h-C2h-C4h were the best points for estimation of the AUC0-12 tacrolimus and MPA (AUC0-12 = 7.04·C0 + 1.71·C2 + 3.23·C4 + 15.19, r2 = 0.799, P < 0.001 and AUC0-12 = 0.26·C0 + 2.06·C2 + 3.82·C4 + 20.38, r2 = 0.693, P < 0.001, respectively). The percent mean error, percent mean absolute error, and percent relative mean square error of the prediction formula using the three time points of C0h-C2h-C4h were -0.3%, 8.8%, and 13.5% for tacrolimus and 2.9%, 17.1%, and 21.5% for MPA, respectively. A limited sampling strategy using C2h-C4h-C9h provides the most reliable and accurate simultaneous estimation of the AUC0-12 of tacrolimus and MPA in patients undergoing renal transplantation. In addition, a limited sampling strategy using C0h-C2h-C4h is recommended for the simultaneous estimation of the AUC0-12 of tacrolimus and MPA when focused on samples collected within 4 hours after administration for clinical expediency.

From the *Department of Pharmacy, Akita University Hospital, Akita, Japan; †Department of Urology, Akita University School of Medicine, Akita, Japan; and ‡Department of Pharmacy, Hirosaki University Hospital, Aomori, Japan.

Received for publication June 20, 2007; accepted October 16, 2007.

Correspondence: Masatomo Miura, PhD, Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita 010-8543, Japan (e-mail: m-miura@hos.akita-u.ac.jp).

© 2008 Lippincott Williams & Wilkins, Inc.