Introduction Despite dosing protocols and tight therapeutic drug monitoring (TDM), tacrolimus concentrations remain highly variable in pediatric liver transplant (LTx) recipients during the first month post-transplantation. The objective of this study was to describe weight-adjusted tacrolimus concentration-to-dose (C/D/kg) ratios and to identify physical, clinical, and laboratory parameters associated with interpatient pharmacokinetic (PK) variability in hospitalized children during the first month post-LTx. Methods In this single-center retrospective cohort study (January 2018–October 2021), we calculated C/D/kg ratios for 36 LTx recipients aged 0–2 years. Descriptive statistics and linear mixed models characterized changes in tacrolimus C/D/kg ratios over time, and we determined the percentage of concentrations within six predefined ranges (0–4, 4–6, 6–8, 8–10, 10–15, and > 15 μg/L). Results In total, 524 trough concentrations of orally administered tacrolimus were analyzed. Tacrolimus C/D/kg ratios ranged from 0.19 to 0.75, demonstrating substantial interpatient variability. Time post-transplantation, alanine aminotransferase, aspartate aminotransferase, total bilirubin, coadministration of corticosteroids, spironolactone, fluconazole, fentanyl, amlodipine, flucloxacillin, and ciprofloxacin were significantly associated with interpatient variability (P < 0.05 for all). In the first week, 40.0% tacrolimus trough concentrations were below 4 μg/L, and using TDM the distribution shifted towards the therapeutic mid-range (6–10 μg/L). Conclusion TDM of tacrolimus is often not enough to obtain the concentrations in the therapeutic range. Identifying cofounders for variability a priori is essential for guiding efficient and accurate dosing, shifting the focus from reactive TDM towards better dosing strategies that improve PK predictions and ultimately improve therapy for pediatric LTx recipients. Graphical Abstract Created with BioRender.com. ALT alanine transaminase, AST aspartate transaminase, C/D/kg weight-adjusted tacrolimus concentration-to-dose, LTx liver transplantation, n number of subjects.<MediaObject ID="MO10"> <ImageObject Color="Color" FileRef="MediaObjects/13318_2025_969_Figa_HTML.png" Format="PNG" Height="1821" Rendition="HTML" Resolution="300" Type="LinedrawHalftone" Width="1498" /> </MediaObject>

Tacrolimus Pharmacokinetics in Pediatric Liver Transplant Recipients During the First Month After Transplantation

期刊论文
发表日期：

2025年11月5日

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Femke A. Elzinga,
Andrea R. Hernandez-Hernandez,
Hubert P. J. van der Doef,
Jos G. W. Kosterink,
Erik A. H. Loeffen,
René Scheenstra,
Arno R. Bourgonje,
Daan J. Touw,
Paola Mian

摘要

Introduction

Despite dosing protocols and tight therapeutic drug monitoring (TDM), tacrolimus concentrations remain highly variable in pediatric liver transplant (LTx) recipients during the first month post-transplantation. The objective of this study was to describe weight-adjusted tacrolimus concentration-to-dose (C/D/kg) ratios and to identify physical, clinical, and laboratory parameters associated with interpatient pharmacokinetic (PK) variability in hospitalized children during the first month post-LTx.

Methods

In this single-center retrospective cohort study (January 2018–October 2021), we calculated C/D/kg ratios for 36 LTx recipients aged 0–2 years. Descriptive statistics and linear mixed models characterized changes in tacrolimus C/D/kg ratios over time, and we determined the percentage of concentrations within six predefined ranges (0–4, 4–6, 6–8, 8–10, 10–15, and > 15 μg/L).

Results

In total, 524 trough concentrations of orally administered tacrolimus were analyzed. Tacrolimus C/D/kg ratios ranged from 0.19 to 0.75, demonstrating substantial interpatient variability. Time post-transplantation, alanine aminotransferase, aspartate aminotransferase, total bilirubin, coadministration of corticosteroids, spironolactone, fluconazole, fentanyl, amlodipine, flucloxacillin, and ciprofloxacin were significantly associated with interpatient variability (P < 0.05 for all). In the first week, 40.0% tacrolimus trough concentrations were below 4 μg/L, and using TDM the distribution shifted towards the therapeutic mid-range (6–10 μg/L).

Conclusion

TDM of tacrolimus is often not enough to obtain the concentrations in the therapeutic range. Identifying cofounders for variability a priori is essential for guiding efficient and accurate dosing, shifting the focus from reactive TDM towards better dosing strategies that improve PK predictions and ultimately improve therapy for pediatric LTx recipients.

Graphical Abstract

Created with BioRender.com. ALT alanine transaminase, AST aspartate transaminase, C/D/kg weight-adjusted tacrolimus concentration-to-dose, LTx liver transplantation, n number of subjects.