https://doi.org/10.1177/1060028017707541 Annals of Pharmacotherapy 1–6 © The Author(s) 2017 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028017707541 journals.sagepub.com/home/aop Research Report Introduction Epilepsy is one of the most common, serious brain disor- ders associated with significant morbidity and mortality. 1,2 Currently, pharmacological management is the mainstay of treatment. Of the available antiepileptic drugs, phenytoin continues to be widely used because of its established effi- cacy based on years of clinical experience. 3 Phenytoin is a highly protein-bound drug (90%) and exhibits nonlinear Michaelis-Menten pharmacokinetics. 3,4 Furthermore, it is associated with significant dose-dependent central nervous system toxicity and gastrointestinal disturbances. 5 Because of its narrow therapeutic window and nonlinear behavior, routine therapeutic drug monitoring is recommended. 3 Because the unbound drug is responsible for the pharma- cological effect, a free phenytoin level may be more accurate in predicting therapeutic response. 6-8 The original Winter- Tozer (WT) equation (Table 1; Equation A) is a frequently cited approximation that has been shown to reliably predict adjusted phenytoin and subsequently free phenytoin levels in normal, healthy patients. 6 Because of the drug’s high affinity to bind to albumin, an increase in free fraction of the drug is anticipated in hypoalbuminemia. The original WT equation adjusts the observed total phenytoin concentration for this effect. However, in patients with end-stage renal disease (ESRD), it is well documented that phenytoin-albumin bind- ing is significantly altered and can affect interpretation of total serum levels. 7-10 Liponi et al 9 found that the binding affinity in ESRD patients was half that of healthy patients. 9 Therefore, a modified WT equation (termed the ESRD WT equation in this article) has been proposed for this patient population despite a lack of supporting data (Table 1; Equation B). 10 The primary 707541AOP XX X 10.1177/1060028017707541Annals of PharmacotherapySoriano et al research-article 2017 1 Rush University Medical Center, Chicago, IL, USA 2 University of Illinois at Chicago, Chicago, IL, USA 3 Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA Corresponding Author: Sean P. Kane, Department of Pharmacy Practice, Rosalind Franklin University of Medicine and Science, 3333 N Green Bay Rd, North Chicago, IL 60064, USA. Email: sean.kane@rosalindfranklin.edu Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation Vincent V. Soriano, PharmD, BCPS 1 , Eljim P. Tesoro, PharmD, BCPS 2 , and Sean P. Kane, PharmD, BCPS 3 Abstract BACKGROUND: The Winter-Tozer (WT) equation has been shown to reliably predict free phenytoin levels in healthy patients. In patients with end-stage renal disease (ESRD), phenytoin-albumin binding is altered and, thus, affects interpretation of total serum levels. Although an ESRD WT equation was historically proposed for this population, there is a lack of data evaluating its accuracy. Objective: The objective of this study was to determine the accuracy of the ESRD WT equation in predicting free serum phenytoin concentration in patients with ESRD on hemodialysis (HD). Methods: A retrospective analysis of adult patients with ESRD on HD and concurrent free and total phenytoin concentrations was conducted. Each patient’s true free phenytoin concentration was compared with a calculated value using the ESRD WT equation and a revised version of the ESRD WT equation. Results: A total of 21 patients were included for analysis. The ESRD WT equation produced a percentage error of 75% and a root mean square error of 1.76 μg/mL. Additionally, 67% of the samples had an error >50% when using the ESRD WT equation. A revised equation was found to have high predictive accuracy, with only 5% of the samples demonstrating >50% error. Conclusion: The ESRD WT equation was not accurate in predicting free phenytoin concentration in patients with ESRD on HD. A revised ESRD WT equation was found to be significantly more accurate. Given the small study sample, further studies are required to fully evaluate the clinical utility of the revised ESRD WT equation. Keywords epilepsy, end-stage renal disease, pharmacokinetics, therapeutic monitoring, anticonvulsants, phenytoin