Predicting Unbound Phenytoin Concentrations: Effects of Albumin Concentration and Kidney Dysfunction

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Clinical Pharmacy
• Nephrology

Background:

• Accurate prediction of unbound (free) phenytoin concentrations is crucial for therapeutic drug monitoring, especially in patients with hypoalbuminemia.
• Existing predictive methods have not been adequately evaluated in patients with combined hypoalbuminemia and kidney dysfunction, or with mild to moderate kidney dysfunction alone.

Purpose of the Study:

• To evaluate the accuracy and precision of various predictive methods for estimating free phenytoin concentrations.
• To assess these methods across a spectrum of albumin concentrations and kidney function levels.

Main Methods:

• Retrospective chart review of 344 patients with recorded phenytoin, albumin, and creatinine levels.
• Application of Winter-Tozer, Anderson, Kane, and Cheng equations for free phenytoin estimation.
• Utilized Shiner-Tozer derivation with adjusted coefficients for patients with reduced estimated glomerular filtration rate (eGFR).
• Evaluated accuracy using P20 (proportion of estimates within 20% of measured free concentration).

Main Results:

• The Anderson method demonstrated the highest accuracy and precision in patients with normal kidney function and varying albumin levels.
• In patients with mild to moderate kidney dysfunction and normal albumin, total phenytoin concentrations accurately reflected free concentrations.
• Predictive method accuracy significantly decreased in patients with hypoalbuminemia combined with kidney dysfunction, particularly with severe impairment.
• No tested coefficient achieved P20 accuracy greater than 45% in patients with severe kidney dysfunction and hypoalbuminemia.

Conclusions:

• In patients with normal albumin and mild/moderate kidney dysfunction (without protein-binding displacers), free phenytoin measurement is unnecessary.
• Direct measurement of free phenytoin concentrations is essential for patients experiencing both hypoalbuminemia and kidney dysfunction.