Population pharmacokinetics of tacrolimus in pediatric liver transplantation: Early posttranplantation clearance

Wallin, Johan E., Bergstrand, Martin, Wilczek, Henryk E., Nydert, Per S., Karlsson, Mats O. and Staatz, Christine E. (2011) Population pharmacokinetics of tacrolimus in pediatric liver transplantation: Early posttranplantation clearance. Therapeutic Drug Monitoring, 33 6: 663-672. doi:10.1097/FTD.0b013e31823415cc

Author Wallin, Johan E.
Bergstrand, Martin
Wilczek, Henryk E.
Nydert, Per S.
Karlsson, Mats O.
Staatz, Christine E.
Title Population pharmacokinetics of tacrolimus in pediatric liver transplantation: Early posttranplantation clearance
Journal name Therapeutic Drug Monitoring   Check publisher's open access policy
ISSN 0163-4356
Publication date 2011-12
Sub-type Article (original research)
DOI 10.1097/FTD.0b013e31823415cc
Volume 33
Issue 6
Start page 663
End page 672
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher Lippincott Williams & Wilkins
Collection year 2012
Language eng
Formatted abstract
Background:Tacrolimus is an immunosuppressant with a narrow therapeutic window, with considerable pharmacokinetic variability. Getting sufficient concentrations in pediatric liver transplantation is imperative, but it has proven difficult in the immediate posttransplantation period in particular. A predictive pharmacokinetic model could be the basis for development of a novel initial dose schedule, and therapeutic drug monitoring with Bayesian methodology.

Methods: The predictive capacity of 2 previously developed population pharmacokinetic models of tacrolimus in pediatric liver transplant recipients was tested in 20 new patients using Bayesian forecasting. Predictive performance was poor in the immediate posttransplant period with tacrolimus pharmacokinetics changing rapidly. A new population pharmacokinetic model, focusing on the immediate posttransplant period, was subsequently developed in 73 patients.

Results: An increase in the apparent clearance of tacrolimus in the first few weeks after transplant was evident. Typical apparent clearance of tacrolimus was 0.148 L·h-1·kg-0.75 immediately after transplantation, increasing to a maximum of 1.37 L·h-1·kg-0.75. Typical apparent distribution volume was 27.2 L/kg. Internal and external validation studies confirmed the predictive capabilities of the developed model. Simulation studies reveal that in 60% of subjects the current initial standard dose without subsequent dosage adjustments overshoot the desired trough concentration range of 10–20 ng/mL. An alternative dosing schedule was developed based on allometric scaling with an initial loading dose followed by a maintenance dose increasing with time.

Conclusions: A population pharmacokinetic model for tacrolimus was developed, to better describe the early posttransplantation phase. This model has the potential to aid therapeutic drug monitoring and was also used to suggest a revised dosing scheme in the intended population.
Keyword Bayesian forecasting
Population pharmacokinetics
Therapeutic drug monitoring
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Pharmacy Publications
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Created: Thu, 15 Dec 2011, 11:20:32 EST by Charna Kovacevic on behalf of School of Pharmacy