Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling

Abstract Background and objective Phenytoin is extensively protein bound with a narrow therapeutic range. The unbound phenytoin is pharmacologically active, but total concentrations are routinely measured in clinical practice. The relationship between free and total phenytoin has been described by v...

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Autores principales:	Heajin Jun, Yan Rong, Catharina Yih, Jordan Ho, Wendy Cheng, Tony K. L. Kiang
Formato:	article
Lenguaje:	EN
Publicado:	Adis, Springer Healthcare 2020
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/39ca7c0df77643c69970309d8cdedeff
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spelling	oai:doaj.org-article:39ca7c0df77643c69970309d8cdedeff2021-12-02T19:16:11ZComparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling10.1007/s40268-020-00323-21174-58861179-6901https://doaj.org/article/39ca7c0df77643c69970309d8cdedeff2020-10-01T00:00:00Zhttps://doi.org/10.1007/s40268-020-00323-2https://doaj.org/toc/1174-5886https://doaj.org/toc/1179-6901Abstract Background and objective Phenytoin is extensively protein bound with a narrow therapeutic range. The unbound phenytoin is pharmacologically active, but total concentrations are routinely measured in clinical practice. The relationship between free and total phenytoin has been described by various binding models with inconsistent findings. Systematic comparison of these binding models in a single experimental setting is warranted to determine the optimal binding behaviors. Methods Non-linear mixed-effects modeling was conducted on retrospectively collected data (n = 37 adults receiving oral or intravenous phenytoin) using a stochastic approximation expectation–maximization algorithm in MonolixSuite-2019R2. The optimal base structural model was initially developed and utilized to compare four binding models: Winter–Tozer, linear binding, non-linear single-binding site, and non-linear multiple-binding site. Each binding model was subjected to error and covariate modeling. The final model was evaluated using relative standard errors (RSEs), goodness-of-fit plots, visual predictive check, and bootstrapping. Results A one-compartment, first-order absorption, Michaelis–Menten elimination, and linear protein-binding model best described the population pharmacokinetics of free phenytoin at typical clinical concentrations. The non-linear single-binding-site model also adequately described phenytoin binding but generated larger RSEs. The non-linear multiple-binding-site model performed the worst, with no identified covariates. The optimal linear binding model suggested a relatively high binding capacity using a single albumin site. Covariate modeling indicated a positive relationship between albumin concentration and the binding proportionality constant. Conclusions The linear binding model best described the population pharmacokinetics of unbound phenytoin in adult subjects and may be used to improve the prediction of free phenytoin concentrations.Heajin JunYan RongCatharina YihJordan HoWendy ChengTony K. L. KiangAdis, Springer HealthcarearticleTherapeutics. PharmacologyRM1-950ENDrugs in R&D, Vol 20, Iss 4, Pp 343-358 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Heajin Jun Yan Rong Catharina Yih Jordan Ho Wendy Cheng Tony K. L. Kiang Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling
description	Abstract Background and objective Phenytoin is extensively protein bound with a narrow therapeutic range. The unbound phenytoin is pharmacologically active, but total concentrations are routinely measured in clinical practice. The relationship between free and total phenytoin has been described by various binding models with inconsistent findings. Systematic comparison of these binding models in a single experimental setting is warranted to determine the optimal binding behaviors. Methods Non-linear mixed-effects modeling was conducted on retrospectively collected data (n = 37 adults receiving oral or intravenous phenytoin) using a stochastic approximation expectation–maximization algorithm in MonolixSuite-2019R2. The optimal base structural model was initially developed and utilized to compare four binding models: Winter–Tozer, linear binding, non-linear single-binding site, and non-linear multiple-binding site. Each binding model was subjected to error and covariate modeling. The final model was evaluated using relative standard errors (RSEs), goodness-of-fit plots, visual predictive check, and bootstrapping. Results A one-compartment, first-order absorption, Michaelis–Menten elimination, and linear protein-binding model best described the population pharmacokinetics of free phenytoin at typical clinical concentrations. The non-linear single-binding-site model also adequately described phenytoin binding but generated larger RSEs. The non-linear multiple-binding-site model performed the worst, with no identified covariates. The optimal linear binding model suggested a relatively high binding capacity using a single albumin site. Covariate modeling indicated a positive relationship between albumin concentration and the binding proportionality constant. Conclusions The linear binding model best described the population pharmacokinetics of unbound phenytoin in adult subjects and may be used to improve the prediction of free phenytoin concentrations.
format	article
author	Heajin Jun Yan Rong Catharina Yih Jordan Ho Wendy Cheng Tony K. L. Kiang
author_facet	Heajin Jun Yan Rong Catharina Yih Jordan Ho Wendy Cheng Tony K. L. Kiang
author_sort	Heajin Jun
title	Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling
title_short	Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling
title_full	Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling
title_fullStr	Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling
title_full_unstemmed	Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling
title_sort	comparisons of four protein-binding models characterizing the pharmacokinetics of unbound phenytoin in adult patients using non-linear mixed-effects modeling
publisher	Adis, Springer Healthcare
publishDate	2020
url	https://doaj.org/article/39ca7c0df77643c69970309d8cdedeff
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Comparisons of Four Protein-Binding Models Characterizing the Pharmacokinetics of Unbound Phenytoin in Adult Patients Using Non-Linear Mixed-Effects Modeling

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