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A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement

BACKGROUND AND OBJECTIVE: Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose ac...

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Autores principales: Andrews, Louise M., de Winter, Brenda C. M., Cornelissen, Elisabeth A. M., de Jong, Huib, Hesselink, Dennis A., Schreuder, Michiel F., Brüggemann, Roger J. M., van Gelder, Teun, Cransberg, Karlien
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217818/
https://www.ncbi.nlm.nih.gov/pubmed/31654367
http://dx.doi.org/10.1007/s40262-019-00831-8
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author Andrews, Louise M.
de Winter, Brenda C. M.
Cornelissen, Elisabeth A. M.
de Jong, Huib
Hesselink, Dennis A.
Schreuder, Michiel F.
Brüggemann, Roger J. M.
van Gelder, Teun
Cransberg, Karlien
author_facet Andrews, Louise M.
de Winter, Brenda C. M.
Cornelissen, Elisabeth A. M.
de Jong, Huib
Hesselink, Dennis A.
Schreuder, Michiel F.
Brüggemann, Roger J. M.
van Gelder, Teun
Cransberg, Karlien
author_sort Andrews, Louise M.
collection PubMed
description BACKGROUND AND OBJECTIVE: Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. METHODS: This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). RESULTS: At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. CONCLUSIONS: The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-019-00831-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-72178182020-05-14 A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement Andrews, Louise M. de Winter, Brenda C. M. Cornelissen, Elisabeth A. M. de Jong, Huib Hesselink, Dennis A. Schreuder, Michiel F. Brüggemann, Roger J. M. van Gelder, Teun Cransberg, Karlien Clin Pharmacokinet Original Research Article BACKGROUND AND OBJECTIVE: Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. METHODS: This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). RESULTS: At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. CONCLUSIONS: The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-019-00831-8) contains supplementary material, which is available to authorized users. Springer International Publishing 2019-10-26 2020 /pmc/articles/PMC7217818/ /pubmed/31654367 http://dx.doi.org/10.1007/s40262-019-00831-8 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research Article
Andrews, Louise M.
de Winter, Brenda C. M.
Cornelissen, Elisabeth A. M.
de Jong, Huib
Hesselink, Dennis A.
Schreuder, Michiel F.
Brüggemann, Roger J. M.
van Gelder, Teun
Cransberg, Karlien
A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement
title A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement
title_full A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement
title_fullStr A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement
title_full_unstemmed A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement
title_short A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement
title_sort population pharmacokinetic model does not predict the optimal starting dose of tacrolimus in pediatric renal transplant recipients in a prospective study: lessons learned and model improvement
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217818/
https://www.ncbi.nlm.nih.gov/pubmed/31654367
http://dx.doi.org/10.1007/s40262-019-00831-8
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