Dataset Information

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

ABSTRACT: BACKGROUND: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. METHODS: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). RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Nakazawa R

PROVIDER: S-EPMC6905578 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Nakazawa Ryuto R Yoshiike Miki M Nozawa Shiari S Aida Koichiro K Katsuoka Yuichi Y Fujimoto Eisuke E Yazawa Masahiko M Kikuchi Eiji E Shibagaki Yugo Y Sasaki Hideo H

PloS one 20191211 12

<h4>Background</h4>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.<h4>Methods</h4>A total of 36 adult ...[more]

PMID: 31825991

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Project description:BackgroundThe 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.MethodsSerum 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.ResultsOne-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).ConclusionThese 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.

Project description:BackgroundTacrolimus is available as twice-daily Prograf® (Tac-BID) and the once-daily formulation, Advagraf® (Tac-OD). Although therapeutically equivalent, some transplant recipients require dose adjustments to achieve similar tacrolimus trough concentrations [Tac C0] after conversion between formulations. Tacrolimus is primarily metabolized by cytochrome P450 3A5 (CYP3A5). We sought to determine whether genetic polymorphisms in the CYP3A5 enzyme; CYP3A5 *1/*1 and CYP3A5 *1/*3 (expressers) compared to CYP3A5 *3/*3 (non-expressers) could account for discrepancies in dose requirements following conversion from Tac-BID to Tac-OD.MethodsA cohort of 60 renal transplant recipients (RTR) from our larger conversion study of 496 patients underwent additional testing for CY3A5 genetic polymorphisms. Analysis included demographics, tac dosing and [Tac C0] pre- and post-conversion and dosing changes relative to CYP3A5 genotypes. CYP3A5 genetic polymorphisms were identified through analysis of genomic DNA.ResultsConversion from tac bid to tac OD in this cohort required a mean (SD) dose increase from 3.1 (1.0) mg/day to 3.8 (1.3) mg/day (p = 0.007), to achieve similar [Tac C0]. The *1/*3 expresser group required a greater percentage dose adjustment (56.7 %) in converting from Tac-BID to Tac-OD as compared to the *3/*3 non-expresser group (26.6 %). Similar findings were observed with the both expresser groups combined (*1/*1 &*1/*3). The expressers were significantly more highly represented in the East Asian cohort.ConclusionsThe CYP3A5 expresser polymorphism necessitates an increase in dosing upon conversion from Tac-BID to Tac-OD, with the expresser genotypes contributing significantly to this finding. Given the variability in frequency of CYP3A5 genotypes in various ethnic groups, future studies should account for both isoenzyme polymorphism and ethnicity in optimizing dosing requirements.Trial registrationClinical trials.gov identifier: NCT01884480.

Dataset Information

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

Publications

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

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