In this episode, I’ll discuss an article about when to draw a free phenytoin level.
Lead author: Margaret C. Montgomery
Published in Pharmacotherapy May 2019
Phenytoin is highly protein bound, and both low albumin levels and renal dysfunction alter the reliability of total phenytoin levels to correlate with free or unbound phenytoin. Because only active medication is the free/unbound medication, this can make interpreting serum levels and adjusting doses especially challenging.
There are several different equations and variations of these equations used to predict free phenytoin concentrations in patients with a low serum albumin. However, these equations have not been evaluated in certain patient populations, most notably those with simultaneous hypoalbuminemia and kidney dysfunction, or in those with only mild to moderate kidney dysfunction.
The authors of this study sought to evaluate the accuracy and precision of predictive methods to estimate free phenytoin concentrations in patients with varying albumin concentrations and/or levels of kidney dysfunction.
The study was a single-center retrospective chart review. Over 300 patient records were analyzed that had free and total phenytoin levels, albumin levels, and serum creatinine concentrations available.
The following equations were used to predict free phenytoin concentrations in patients without kidney dysfunction:
For patients with an eGFR <90 mL/min/1.73 m2, free phenytoin concentrations were predicted using the Shiner‐Tozer derivation with four different affinity coefficients (0.15, 0.20, 0.25, and 0.30).
The accuracy of the predictive methods was evaluated by the proportion of estimations within 20% of the measured free phenytoin concentration.
The Anderson method for predicting free phenytoin concentrations had the highest accuracy and precision for patients scoring 82% or better in the following groups:
- Those with normal kidney function/normal albumin concentrations
- Those with normal kidney function/hypoalbuminemia
- Those with mild kidney dysfunction/normal albumin concentrations
The following groups of patients had the free fraction unchanged and total phenytoin concentrations were predictive of free phenytoin:
- Those with normal albumin concentrations and mild kidney dysfunction
- Those with normal albumin concentrations and moderate kidney dysfunction
The following groups of patients had accuracy and precision no better than 67%, despite the formula used:
- Those with hypoalbuminemia and any level of kidney dysfunction
The authors concluded:
In patients with normal albumin concentrations, with or without mild or moderate kidney dysfunction and not receiving a protein‐binding displacer, the free fraction of phenytoin is unchanged, and it is not necessary to measure a free phenytoin concentration. Free phenytoin concentrations should be measured directly in patients with hypoalbuminemia and kidney dysfunction.
In addition to accuracy, the cost and turn-around time of free phenytoin levels compared with total levels are important variables. In a perfect world, only free phenytoin levels would be used to evaluate phenytoin concentrations. Depending on the resources available, routinely checking free phenytoin levels may be considered costly and time-consuming. A conversation with your laboratory’s chemistry department can answer the cost and turn around time questions and help determine how much discretion you need to use when considering whether to check a free or total phenytoin level.
Assuming that some discretion is necessary, this article provides excellent guidance for checking free phenytoin levels only in the presence of simultaneous hypoalbuminemia and kidney dysfunction.
Additional reasons to check free phenytoin levels not covered in this article are in patients receiving other albumin-bound medications that could displace phenytoin such as valproic acid, or in overdose situations where binding sites may saturate and a free level may provide better guidance for treatment decisions.
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