Phenytoin (Dilantin) Correction for Albumin / Renal Failure
Use in patients with albumin ≤3.2 g/dL (32 g/L).
Patients taking phenytoin who have renal failure or albumin ≤3.2 g/dL (32 g/L).
Phenytoin has a narrow therapeutic window, and is highly protein-bound. The protein-bound phenytoin is what is typically measured by the lab. However, unbound phenytoin is the active portion (it crosses the blood-brain barrier). This calculator helps estimate the equivalent active amount of phenytoin based on typical lab values.
Helps avoid under- or over-dosing in patients with renal failure or low albumin.
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Adjust phenytoin dosing based on values.
If consistently out of range, consider other antiepileptics.
Concomitant use of valproic acid and some other drugs displaces phenytoin from plasma proteins and can lead to erratic levels.
Whenever possible, a free phenytoin level should be utilized over a corrected level.
A therapeutic phenytoin level is generally considered to be 10-20 mg/L (40-80 µmol/L). Levels above this may cause nystagmus, ataxia, lethargy, confusion, and coma.
Corrected phenytoin = measured phenytoin level / ( (adjustment x albumin) + 0.1)
Adjustment = 0.275; in patients with creatinine clearance <20 mL/min, adjustment = 0.2.
Note: no correction is needed for albumin >3.2. This calculation is derived from the original Winter-Tozer formula, which used an albumin coefficient of 0.2, and 0.1 for renal failure.
Facts & Figures
The “Sheiner-Tozer Equation” is the official name of this correction.
Phenytoin is highly protein bound, but generally it is the free, unbound portion in the serum that correlates with concentrations within the central nervous system (Vadja 2014). Laboratories typically only measure the bound portion of phenytoin. Many equations to predict unbound phenytoin concentrations have been developed. The Winter-Tozer formula (also known as Sheiner-Tozer) is one of the most widely used equations (Sheiner 1978). However, this equation was derived by using pharmacokinetics from subjects who were otherwise healthy (Martin 1977). Subsequent research has shown it to be less accurate in critically ill patients with renal failure or low albumin.
The original formulas used an albumin binding coefficient (see below) of 0.2, and 0.1 for patients with renal failure (Winter 2006). These equations assumed a normal serum albumin and an unbound drug portion of 10%. However, these coefficients have been found to be inaccurate, especially when serum albumin levels are low (Hong 2009), or when renal function is poor (Liponi 1984).
Different coefficients have shown better correlations with free phenytoin levels, ranging from 0.25 in the elderly and in head trauma (Anderson 1997) to 0.29 in neurointensive care patients (Kane 2013). Another study comprised of general medicine, neurology, and intensive care patients showed a coefficient of 0.275 to be most predictive (Cheng 2016). For this calculator, a coefficient of 0.275 was used for non-renal failure, which was felt to represent a compromise between the trauma and ICU studies, and had been derived from the most diverse patient sample.
Less is known about phenytoin in renal failure, but at least one smaller study supports a coefficient of 0.2 in these patients (Soriano 2017). However, it should be noted that none of these equations has been validated by a prospective trial, and whenever possible, free phenytoin levels should be used to guide therapy.
Original/Primary ReferenceMartin E, Tozer TN, Sheiner LB, Riegelman S. The clinical pharmacokinetics of phenytoin. J Pharmacokinet Biopharm. 1977 Dec;5(6):579-96.Sheiner LB, Tozer TN. Clinical pharmacokinetics: the use of plasma concentrations of drugs. In: Melmon KL, Morelli HF, editors. Clinical Pharmacology: Basic Principles in Therapeutics. New York: Macmillan; 1978. p.71-109.Winter MG, Tozer TN. Chapter 20. Phenytoin. In: Burton ME, Shaw LM, Schentag JJ, Evans WE. Applied pharmacokinetics: principles of therapeutic drug monitoring. 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, ©2006.
Other ReferencesVajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic drugs. Epileptic Disord. 2014;16:395-408.Hong JM, Choi YC, Kim WJ. Differences between the Measured and Calculated Free Serum Phenytoin Concentrations in Epileptic Patients. Yonsei Medical Journal. 2009;50(4):517-520.Liponi DF, Winter ME, Tozer TN. Renal function and therapeutic concentrations of phenytoin. Neurology 1984;34:395-7.Kane SP, Bress AP, Tesoro EP. Characterization of unbound phenytoin concentrations in neurointensive care unit patients using a revised Winter-Tozer equation. Ann Pharmacother. 2013;47(5):628-36.Anderson GD, Pak C, Doane KW, et al. Revised Winter-Tozer equation for normalized phenytoin concentrations in trauma and elderly patients with hypoalbuminemia. Ann Pharmacother. 1997;31(3):279-84.Cheng W, Kiang TKL, Bring P, Ensom MHH. Predictive Performance of the Winter–Tozer and Derivative Equations for Estimating Free Phenytoin Concentration. The Canadian Journal of Hospital Pharmacy. 2016;69(4):269-279.Soriano VV, Tesoro EP, Kane SP. Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation. Ann Pharmacother. 2017;:1060028017707541.Kiang TK, Ensom MH. A Comprehensive Review on the Predictive Performance of the Sheiner-Tozer and Derivative Equations for the Correction of Phenytoin Concentrations. Ann Pharmacother. 2016;50(4):311-25.
About the Creator
Thomas N. Tozer, PhD, PharmD, BS, is professor emeritus of biopharmaceutical sciences and pharmaceutical chemistry at School of Pharmacy at UCSF. He is the co-author of Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications. Prior to retirement, Dr. Tozer researched colon-specific drug delivery, toxicokinetics, kinetics of potential contrast agents for magnetic resonance imaging and nonlinear pharmacokinetics.
To view Dr. Thomas N. Tozer's publications, visit PubMed
- Andrew Michalak, MD