Limited Sampling Strategies for Monitoring Tacrolimus in Pediatric Liver Transplant Recipients
ABSTRACT To develop and validate limited sampling strategies (LSSs) for tacrolimus in pediatric liver transplant recipients.
Thirty-six 12-hour pharmacokinetic profiles from 28 pediatric liver transplant recipients (0.4-18.5 years) were collected. Tacrolimus concentrations were measured by immunoassay and area under the curve (AUC0-12) was determined by trapezoidal rule. LSSs consisting of 1, 2, 3, or 4 concentration-time points were developed using multiple regression analysis. Eight promising models (2 per category) were selected based on the following criteria: r2 ≥ 0.90, inclusion of trough concentration (C0), and time points within 4 hours postdose. The predictive performance of these LSSs was evaluated in an independent set of data by measuring the mean prediction error and the root mean squared prediction error.
Five models including 2-4 time points predicted AUC0-12 with a ±15% error limit. Bias (mean prediction error) and precision (root mean squared prediction error) of LSS involving C0, C1, and C4 (AUCpredicted = 9.30 + 3.69 × C0 + 2.19 × C1 + 4.69 × C4) were -4.98% and 8.29%, respectively. Among single time point LSSs, the model using C0 had a poor correlation with AUC0-12 (r2 = 0.53), whereas the one with C4 had the highest correlation with tacrolimus exposure (r2 = 0.84).
Trough concentration is a poor predictor of tacrolimus AUC0-12 in pediatric liver transplant recipients. However, LSSs using 2-4 concentration-time points obtained within 4 hours postdose provide a reliable and convenient method to predict tacrolimus exposure in this population. The proposed LSSs represent an important step that will allow the undertaking of prospective trials aiming to better define tacrolimus target AUC in pediatric liver transplant recipients and to determine whether AUC-guided monitoring is superior to C0-based monitoring in terms of efficacy and safety.
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ABSTRACT: A bioanalytical method for the quantification of tacrolimus (TAC) on dried blood spots (DBS) using liquid chromatography, electrospray ionization coupled with tandem mass spectrometry (LC-ESI-MS/MS) was developed and validated. It involves solvent extraction of a punch disk of DBS followed by liquid-liquid extraction. The analyte and the internal standard (IS, ascomycin) were separated on a phenyl column using an isocratic mobile phase elution at a flow rate of 0.3 mL/min. The assay was linear from 1 to 80 ng/mL. The mean recovery of TAC was 76.6%. Intra-assay, inter-assay imprecision and biases were all less than 15%. TAC on DBS was stable for at least 10 days at room temperature, and at least 24 h at 50°C. A chromatographic effect of the filter paper (Whatman 903) was not detected. The volume of blood (15-50 μL) and hematocrit of blood (ranging from 23.2 to 48.6%) did not show a significant influence on detection of TAC concentration by DBS-LC-MS/MS. Fifty samples from patients were detected by both DBS-LC-MS/MS and microparticle enzyme-linked immunoassay (MEIA). TAC concentrations measured by DBS-LC-MS/MS method tended to be lower than those by MEIA. Copyright © 2012 John Wiley & Sons, Ltd.Biomedical Chromatography 08/2012; 27(3). DOI:10.1002/bmc.2795 · 1.72 Impact Factor
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ABSTRACT: Background: A limited sampling strategy (LSS) for estimating the area under the curve (AUC) of the prolonged-release formulation of tacrolimus (tacrolimus(PR)) is not available in pediatric patients, although the method is of real benefit to children. The objective of this study was to develop and validate a reliable and clinically applicable LSS using Bayesian estimation for estimating tacrolimus(PR) AUC in pediatric kidney transplant patients Methods: The original tacrolimus pharmacokinetic dataset consisted of 22 full profiles from 22 pediatric kidney transplant patients. The Bayesian estimation method was used to develop the LSS. External validation was performed in an independent validation group which consisted of 20 full pharmacokinetic profiles from 12 pediatric kidney transplant patients. Results: Bayesian estimator using C0h C2h and C3h gave the best predictive performance with a mean prediction error of 2.2 % in the external validation dataset. There was no correlation between the prediction error and age. The Bland-Altman analysis showed that the mean difference between the reference and Bayesian-estimated AUC0-24 was 3.5 (95 % confidence interval -3.5-10.5) ng h/mL CONCLUSIONS: A reliable and clinically applicable LSS for estimating AUC0-24 of tacrolimus(PR) was determined and validated in children. The prediction was unbiased and precise. It can be used as a routine procedure to perform AUC-based tacrolimus(PR) dosage optimization in pediatric renal transplant patients.European Journal of Clinical Pharmacology 12/2012; 69(5). DOI:10.1007/s00228-012-1457-5 · 2.97 Impact Factor
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ABSTRACT: The pharmacokinetics of tacrolimus, one of the most widely used immunosuppressive drugs, are known to vary by sex, age, and ethnicity during pediatric transplantation. This study assessed the pharmacokinetic characteristics and associated factors of tacrolimus in Korean children receiving a kidney transplant.Journal of the Korean Society of Pediatric Nephrology 01/2014; 18(1):18. DOI:10.3339/jkspn.2014.18.1.18