Characterization of Unbound Phenytoin Concentrations in Neurointensive Care Unit Patients Using a Revised Winter-Tozer Equation

Kane, Sean P.; Bress, Adam P.; Tesoro, Eljim P.

doi:10.1345/aph.1r651

Cited by 22 publications

(60 citation statements)

References 16 publications

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“…Only a limited number of laboratories offer this service. Thus various equations for predicting an unbound concentration have been developed and validated for phenytoin . However, to our knowledge, no equation for predicting unbound VPA concentration is available in clinical practice.…”

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confidence: 99%

“…Indirect methods for estimating the free fraction of VPA were proposed, as well as a total VPA concentration correction model for albumin based on the estimation of the free fraction (free fraction [%] = 130.69∙e (−0.00496∙serum albumin concentration) , where albumin is expressed in μmol/L) . These methods have not been validated and are not practical, unlike equations developed for phenytoin . Therefore, these models have not replaced the determination of unbound VPA concentration in clinical practice.…”

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confidence: 99%

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Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

2017

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This study showed that in the presence of hypoalbuminemia, high unbound VPA concentrations can be observed despite normal or low total VPA concentrations. It also demonstrated that high unbound VPA concentrations are associated with clinically significant neurologic adverse symptoms. Clinicians should be aware that unbound VPA concentration monitoring may be required in the presence of hypoalbuminemia.

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confidence: 99%

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confidence: 99%

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

2017

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“…Two reports showed the original Winter‐Tozer equation overestimated and another showed it underestimated the measured free phenytoin concentration, leading to erroneous dosing changes in different patient populations. This was shown in the elderly nursing home population and in neurotrauma patients, in critically ill patients, and in critical care, general medicine, and neurology units . In the current study, all four equations were evaluated to see if these results would hold true at a large multisite academic medical center.…”

Section: Discussionmentioning

confidence: 99%

“…Four published methods are available for predicting free phenytoin concentrations in patients with hypoalbuminemia: Winter‐Tozer, Anderson, Kane, and Cheng (Table ). For the Winter‐Tozer method, the constant 0.2 in the original derivation was determined to be a measurement of the drug‐binding affinity at an albumin concentration of 4.4 g/dl measured at 37°C in individuals with epilepsy.…”

Section: Predictive Equations For Estimating Free Phenytoin Concentramentioning

confidence: 99%

“…The objectives of this study were to determine the predictive ability of the Winter‐Tozer, Anderson, Kane, and Cheng methods in estimating free phenytoin concentrations in patients with varying albumin concentrations, and to develop revised equations to reflect the degree of kidney dysfunction.…”

Section: Predictive Equations For Estimating Free Phenytoin Concentramentioning

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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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Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review

Lin

Cao

Au³

et al. 2022

Clin Pharmacokinet

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Characterization of Unbound Phenytoin Concentrations in Neurointensive Care Unit Patients Using a Revised Winter-Tozer Equation

Cited by 22 publications

References 16 publications

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

Clinical Importance of Monitoring Unbound Valproic Acid Concentration in Patients with Hypoalbuminemia

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

Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review

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