Phenytoin Correction Calculator

Dilantin correction calculator for hypoalbuminemia

Patient Parameters

Albumin
Total phenytoin

Correction Factors

ESRD: Question

Press 'Calculate' to view calculation results.

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.

Corrected Total Phenytoin Level

In patients with hypoalbuminemia, a corrected equation must be used to account for reduced phenytoin protein binding. This calculator uses the following revised Winter-Tozer correction equation, which was validated in a neurosurgical intensive care unit patient population. Note that this equation is a variant of the traditional Winter-Tozer equation, which has been demonstrated to be less accurate.3

$$\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{0.29 * Albumin + 0.1}$$

For those with significant uremia (CrCl < 10 mL/min or hemodialysis), an alternative correction equation is used:4

$$\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{0.1 * Albumin + 0.1}$$

Traditional Winter-Tozer Equation

The original Winter-Tozer equation4 (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' was originally suggested to calculate a corrected phenytoin level in patients without significant comorbidities.5 In patients with renal dysfunction or end-stage renal disease, a coefficient of '0.1' is considered to be more appropriate due to reduced protein binding secondary to uremia, although this method has been shown to poorly correlated with free phenytoin levels.4,6

$$ \\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{\frac{Albumin}{4.4}*0.9+0.1} \\ \\ \\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{0.2 * Albumin + 0.1} \\ \\ Renal\;dysfunction: \\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{0.1 * Albumin + 0.1} $$

Inaccuracies of the Traditional Winter-Tozer Equation

There is considerable controversy regarding the accuracy of the traditional Winter-Tozer equation. As previously mentioned, the traditional Winter-Tozer equation has repeatedly been shown to overpredict corrected phenytoin levels.6 At least two equations, using a coefficient of 0.25 or 0.29, have been suggested to improve the accuracy of a corrected phenytoin level.3,7 Despite the preponderance of data against the traditional Winter-Tozer equation, recent articles still support its use, particularly if the phenytoin assay is run at body temperature (not room temperature).8

Correction Factors for this Calculator

On the basis of available literature, the following coefficients are provided by this clinical calculator:

Coefficient Comments Citation
0.1 Suggested for end-stage renal disease patients -- likely inaccurate 4,6
0.2 Traditional (original) Winter-Tozer equation -- likely inaccurate for laboratories that run the phenytoin assay at room temperature 4,8,1,2
0.25 Revised Winter-Tozer equation studied in elderly patients and severe head trauma; significantly more accurate than the traditional equation 7
0.29 Revised Winter-Tozer equation studied in neurointensive care unit patients; significantly more accurate than the traditional equation 3

References and Additional Reading

  1. May TW, Rambeck B, J├╝rges 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.
  2. Soldin SJ. Free drug measurements. When and why? An overview. Arch Pathol Lab Med. 1999;123(9):822-3. PMID 10458831.
  3. 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. PMID 23606554.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.

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Updated Sep 9, 2014
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