About This Calculator
Due to its narrow therapeutic index and non-linear pharmacokinetic profile, phenytoin therapeutic drug monitoring is recommended. Because phenytoin is highly protein bound and only unbound drug is capable of crossing the blood-brain barrier to exert its pharmacologic effect, unbound (free) phenytoin levels may be more clinically relevant than total levels to maximize efficacy and minimize toxicity.1,2
Although unbound (free) phenytoin levels can be measured by a laboratory assay, this method may not be available on-site at all institutions, or the turnaround time for a result may be so long that it limits its clinical utility. The Winter-Tozer equation was developed to help clinicians estimate an unbound (free) phenytoin concentration based on a total phenytoin level and a serum albumin level.
Winter-Tozer Equation
The original Winter-Tozer equation3 (displayed below) was initially developed in patients with epilepsy assuming a normal serum albumin of 4.4 g/dL and a free fraction of 10%. By simplifying the equation, a coefficient of '0.2' has demonstrated good correlation to free phenytoin concentrations in most patients without significant comorbidities.4 In patients with renal dysfunction or end-stage renal disease, a coefficient of '0.1' may be more appropriate due to reduced protein binding secondary to uremia.3
\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{\frac{Albumin}{4.4}*0.9+0.1}
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\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{0.2 * Albumin + 0.1}
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\\ Renal\;dysfunction:
\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{0.1 * Albumin + 0.1}
Correction Factors
There is considerable controversy regarding the accuracy of the Winter-Tozer equation in a variety of patient populations. In a study of patients with hypoalbuminemia and normal renal function (CrCl > 50 mL/min and albumin < 4.0 g/dL), the Winter-Tozer equation (using a coefficient of 0.2) significantly underpredicted true free phenytoin concentrations.5 In the same study,5 the Winter-Tozer equation (using a coefficient of 0.1) was poorly correlated to true free concentrations in patients with renal failure on dialysis.
In critically ill patients, the Winter-Tozer equation may be problematic due to a high incidence of renal dysfunction, large changes in fluid status, and hypoalbuminemia. While one study of neurosurgical patients showed a strong correlation,6 other literature suggests that a coefficient of '0.25' may be more appropriate, particularly in elderly patients or patients with severe head trauma.7
Correction Factors for this Calculator
On the basis of available literature, the following coefficients are used by this clinical calculator:
- No comorbidities: 0.2 1-3
- ESRD: 0.1 1
- Severe head trauma: 0.25 7
- Age > 65 years: 0.25 7
References 
- May TW, Rambeck B, Jürges U, et al. Comparison of total and free phenytoin serum concentrations measured by high-performance liquid chromatography and standard TDx assay: implications for the prediction of free phenytoin serum concentrations. Ther Drug Monit. 1998;20(6):619-23. PMID 9853976
- Soldin SJ. Free drug measurements. When and why? An overview. Arch Pathol Lab Med. 1999;123(9):822-3. PMID 10458831
- Winter MG, Tozer TN. Chapter 25. Phenytoin. In: Evans WE, Schentag JJ, Jusko WJ. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3rd ed. Vancouver, WA: Applied Therapeutics, 1992:1-44.
- Hong JM, Choi YC, Kim WJ. Differences between the measured and calculated free serum phenytoin concentrations in epileptic patients. Yonsei Med J. 2009;50(4):517-20. PMID 19718399
- Mauro LS, Mauro VF, Bachmann KA, et al. Accuracy of two equations in determining normalized phenytoin concentrations. DICP. 1989;23(1):64-8. PMID 2718487
- Mlynarek ME, Peterson EL, Zarowitz BJ. Predicting unbound phenytoin concentrations in the critically ill neurosurgical patient. Ann Pharmacother. 1996;30(3):219-23. PMID 8833553
- 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. PMID 9066931