# Phenytoin Correction Calculator

## Dilantin correction calculator for hypoalbuminemia

### Patient Parameters

 Albumin g/dL Total phenytoin mcg/mL

### Correction Factors

 Dialysis or ESRD: No Yes Concurrent valproic acid: No Yes

RESULTS

#### Corrected Total Phenytoin Level

14.2 mcg/mL
(goal 10 to 20 mcg/mL)

The corrected total phenytoin level is WITHIN goal (assuming a goal of 10 to 20 mcg/mL).

Be advised that obtaining a free phenytoin level is preferred over a total phenytoin correction equation when monitoring therapy; however, this correction equation exists for scenarios in which a free level cannot be readily obtained or is too costly for routine use.1,2

#### Estimated Free Phenytoin Level

1.4 mcg/mL
(goal 1 to 2 mcg/mL)

Assuming 10% protein binding, the estimated free phenytoin level is WITHIN goal (assuming a goal of 1 to 2 mcg/mL).

Although 10% protein binding is most typical, the free fraction (percent protein binding) of phenytoin varies between patients. It is recommended to obtain a free phenytoin level whenever possible.1,2

$$\\ \textbf{Method #1 (coefficient = 0.25):}\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{Coefficient * Albumin + 0.1}\\ Corrected\;phenytoin = \frac{(11\;mcg/mL)}{0.25 * 2.5 + 0.1} = 15.2\;mcg/mL\\~ \\~ \\ \textbf{Method #2 (coefficient = 0.29):}\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{Coefficient * Albumin + 0.1}\\ Corrected\;phenytoin = \frac{(11\;mcg/mL)}{0.29 * 2.5 + 0.1} = 13.3\;mcg/mL\\~ \\~ \\ \textbf{Mean value from method #1 and #2} = 14.2\;mcg/mL$$

What does the 'coefficient' in the equation mean?

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.3,4

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 revised versions of the Winter-Tozer correction equation for patients with normal renal function and those with end-stage renal disease. The original Winter-Tozer equations for these two patient populations have consistently been shown to be inaccurate, although one may still find the original equations in textbooks or other resources.1,2,5

$$\\ \textbf{Patients without end-stage renal disease:} \\ Corrected\;phenytoin\;(equation\;1) = \frac{(Measured\;phenytoin)}{0.25 * Albumin + 0.1} \\ Corrected\;phenytoin\;(equation\;2) = \frac{(Measured\;phenytoin)}{0.29 * Albumin + 0.1} \\ ~ \\ ~ \\ \textbf{Patients WITH end-stage renal disease or significant uremia:} \\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{0.2 * Albumin + 0.1}$$

The original Winter-Tozer equation6 (displayed below) was 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.7 In patients with renal dysfunction or end-stage renal disease, a coefficient of '0.1' was considered to be more appropriate due to reduced protein binding secondary to uremia, although this method has now been shown to poorly correlated with free phenytoin levels.6,8 When used in the Winter-Tozer equation, both of these coefficients are inaccurate and should not be used.

$$\\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{\frac{Albumin}{4.4}*0.9+0.1} \\ ~ \\ Corrected\;phenytoin = \frac{(Measured\;phenytoin)}{Coefficient * Albumin + 0.1}$$

#### 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.8 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 among patients without severe renal impairment.1,5 In addition, the historical equation designed for renal impairment (end-stage renal disease, severe uremia, or hemodialysis) has also been updated to improve the accuracy of the equation.2 Despite the preponderance of data against the original Winter-Tozer equations, recent articles still support its use, particularly if the phenytoin assay is run at body temperature (not room temperature).9

#### Correction Factors for this Calculator

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

 Coefficient Comments Citation 0.25 Revised Winter-Tozer equation studied in elderly patients and severe head trauma; significantly more accurate than the traditional equation 5 0.29 Revised Winter-Tozer equation studied in neurointensive care unit patients; significantly more accurate than the traditional equation 1 0.2 Revised Winter-Tozer equation for patients with end-stage renal disease, severe uremia, or hemodialysis. Due to a small sample size supporting this revised equation, free phenytoin levels are strongly recommended whenever possible. 2

Because of limitations in the data, it is not clear whether a coefficient of 0.25 or 0.29 is superior in patients without renal impairment.1,5 For this reason, the calculator will report the average value between these two estimates. The individual values can be reviewed by clicking the "Equations" tab within the results area.

1. 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.
2. Soriano VV, Tesoro EP, Kane SP. Characterization of Free Phenytoin Concentrations in End-Stage Renal Disease Using the Winter-Tozer Equation. Ann Pharmacother. 2017 May 1:1060028017707541. doi: 10.1177/1060028017707541. PMID 28470115.
3. 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.
4. Soldin SJ. Free drug measurements. When and why? An overview. Arch Pathol Lab Med. 1999;123(9):822-3. PMID 10458831.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.