Clinically useful limited sampling strategy to estimate area under the concentration-time curve of once-daily tacrolimus in adult Japanese kidney transplant recipients

Autoři: Ryuto Nakazawa aff001;  Miki Yoshiike aff001;  Shiari Nozawa aff001;  Koichiro Aida aff001;  Yuichi Katsuoka aff001;  Eisuke Fujimoto aff001;  Masahiko Yazawa aff002;  Eiji Kikuchi aff001;  Yugo Shibagaki aff002;  Hideo Sasaki aff001
Působiště autorů: Department of Urology, St. Marianna University School of Medicine, Kawasaki, Japan aff001;  Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225878



An extended-release, once-daily, oral formulation of tacrolimus is currently used after kidney transplantation as a substitute for the conventional twice-daily formulation. The purpose of this study was to provide a limited sampling strategy with minimum and optimum sampling points to predict the tacrolimus area under the concentration-time curve (AUC) after administration of once-daily tacrolimus in de novo adult kidney transplant patients.


A total of 36 adult Japanese kidney transplant patients receiving once-daily tacrolimus were included: 31 were allocated to a study group to develop limited sampling strategy (LSS) model equations based on multiple stepwise linear regression analysis, and 5 were allocated to a validation group to estimate the precision of the LSS equations developed by the study group. Twelve-hour AUC (AUC0-12) was calculated by the trapezoidal rule, and the relationship between individual concentration points and AUC0-12 were determined by multiple linear regression analysis. The coefficient of determination (R2) was used to assess the goodness-of-fit of the regression models. Three error indices (mean error, mean absolute error, and root mean squared prediction error) were calculated to evaluate predictive bias, accuracy, and precision, respectively. Quality of the statistical models was compared with Akaike's information criterion (AIC).


A four-point model using C0, C2, C4 and C6 gave the best fit to predict AUC0-12 (R2 = 0.978). In the three- and two-point models, the best fits were at time points C2, C4, and C6 (R2 = 0.973), and C2 and C6 (R2 = 0.962), respectively. All three models reliably estimated tacrolimus AUC0-12, consistent with evaluations by the three error indices and Akaike’s information criterion. Practically, the two-point model with C2 and C6 was considered to be the best combination, providing a highly accurate prediction and the lowest blood sampling frequency.


The two-point model with C2 and C6 may be valuable in reducing the burden on patients, as well as medical costs, for once-daily tacrolimus monitoring.

Klíčová slova:

Approximation methods – Blood – Dose prediction methods – Oral administration – Pharmacokinetics – Renal transplantation – Therapeutic drug monitoring


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