Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation

Soriano, Vincent; Tesoro, Eljim P.; Kane, Sean P.

doi:10.1177/1060028017707541

Cited by 15 publications

(17 citation statements)

References 9 publications

(24 reference statements)

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“…One report investigated the modified Winter-Tozer equation (C = 0.1) in 21 patients with ESRD who were receiving hemodialysis and had a mean serum albumin concentration of 2.8 AE 0.7 g/ dl. 32 In the analysis, 67% of the samples had an error greater than 50% with the modified Winter-Tozer method. The original Winter-Tozer equation (C = 0.2) developed for patients without kidney dysfunction was significantly more accurate.…”

Section: Discussionmentioning

confidence: 94%

“…The Winter‐Tozer ( C = 0.2) and a modified Winter‐Tozer ( C = 0.1) equations under‐ or overpredicted normalized phenytoin concentrations by at least 25% in half of the patients. One report investigated the modified Winter‐Tozer equation ( C = 0.1) in 21 patients with ESRD who were receiving hemodialysis and had a mean serum albumin concentration of 2.8 ± 0.7 g/dl . In the analysis, 67% of the samples had an error greater than 50% with the modified Winter‐Tozer method.…”

Section: Discussionmentioning

confidence: 99%

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Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction

et al. 2019

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Study Objective Several methods are available to predict unbound (free) phenytoin concentrations in patients with hypoalbuminemia; however, predictive methods have not been evaluated in patients with concurrent hypoalbuminemia and kidney dysfunction or in patients with mild to moderate (estimated glomerular filtration rate [eGFR] 30‐90 ml/min/1.73 m2) kidney dysfunction alone. Thus the objective was to evaluate the accuracy and precision of predictive methods to estimate free phenytoin concentrations in patients with varying albumin concentrations and/or kidney dysfunction. Design Retrospective chart review. Setting Large academic medical center. Patients A total of 344 patients with free and total phenytoin, albumin, and serum creatinine concentrations obtained between November 2012 and May 2017. Measurements and Main Results Free phenytoin concentrations were estimated in patients without kidney dysfunction using the Winter‐Tozer, Anderson, Kane, and Cheng equations. For the analysis in patients with eGFR lower than 90 ml/min/1.73 m2, free phenytoin concentrations were estimated using the Shiner‐Tozer derivation with adjusted affinity coefficients (C = 0.15, 0.20, 0.25, and 0.30). For both analyses, accuracy of predictive methods was evaluated by P20, the proportion of estimations within 20% of the measured free phenytoin concentration. In 158 patients with normal kidney function/normal albumin concentrations, 73 with normal kidney function/hypoalbuminemia, or 47 with mild kidney dysfunction/normal albumin concentrations, the Anderson method had the highest accuracy (86%, 82%, and 92%, respectively) and highest precision compared with the other methods. In 47 patients with normal albumin concentrations and mild kidney dysfunction or 13 with moderate kidney dysfunction, the free fraction was unchanged, and total phenytoin concentrations accurately reflected free concentrations. In 17 patients with hypoalbuminemia and mild or 17 with moderate kidney dysfunction, the Winter‐Tozer (67% and 50%, respectively) and the Anderson (56% and 67%, respectively) methods had the highest accuracy compared with other methods with significantly lower accuracy compared with patients with normal kidney function. In the 14 patients with severe kidney dysfunction and hypoalbuminemia, none of the coefficients had a P20 accuracy greater than 45%. Conclusion In patients with normal albumin concentrations, with or without mild or moderate kidney dysfunction and not receiving a protein‐binding displacer, the free fraction of phenytoin is unchanged, and it is not necessary to measure a free phenytoin concentration. Free phenytoin concentrations should be measured directly in patients with hypoalbuminemia and kidney dysfunction.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction

et al. 2019

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“…To describe the elimination of free phenytoin, we examined linear and Michaelis-Menten models. Based on the literature [19][20][21][22][23][24][25][30][31][32], protein-binding relationships of phenytoin could be characterized by four types of binding-dissociation models, described as follows:…”

Section: Base Model Selectionmentioning

confidence: 99%

“…Several combinations of structural, protein binding, and error models were tested ( Table 2). A systematic approach was implemented to identify the most suitable base model: (1) initial search of the best model without considering protein binding (i.e., models 1-12 in Table 2), (2) screening of four different binding models that best complemented the identified structural model (i.e., models [13][14][15][16], and 3testing for the optimal residual error models (i.e., models [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. For the structural model, the Michaelis-Menten elimination model was used because the free phenytoin concentrations in our dataset (1.4 ± 0.7 mg/L) exceeded the literature-estimated (0.40-0.73 mg/L [26,44]) and modelestimated Km values (Table 3).…”

Section: Base Model Selectionmentioning

confidence: 99%

“…Several approaches have been proposed to describe the relationship between free and total phenytoin by characterizing the binding of free phenytoin with serum albumin. The most widely used approach is the Winter-Tozer equation, which has been modified by many others to better tailor to individual patient populations [19][20][21][22][23]. Moreover, non-linear mixed-effects modeling has been used to predict unbound phenytoin concentrations and characterize the nature of protein binding.…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2020

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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-bindingsite 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.

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Free versus total phenytoin measurements—a case study of phenytoin toxicity

Paul

Robinson

Sadrzadeh

2020

Toxicology Cases for the Clinical and Forensic Laboratory

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Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation

Cited by 15 publications

References 9 publications

Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction

Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction

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

Free versus total phenytoin measurements—a case study of phenytoin toxicity

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