Phenytoin Correction Calculator
Dilantin correction calculator for hypoalbuminemia
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 equation^{4} (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:
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
- 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.
- 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.
- 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.
- 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.
- 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.