A graphical nomogram method for predicting toxic concentrations of unbound phenytoin

Area of Science:

• Pharmacokinetics
• Clinical Chemistry
• Analytical Chemistry

Background:

• Accurate monitoring of serum phenytoin concentration is crucial for therapeutic efficacy and toxicity management.
• Phenytoin is a widely used anticonvulsant drug with a narrow therapeutic index.
• Estimating free (unbound) phenytoin concentration is often more clinically relevant than total concentration.

Purpose of the Study:

• To develop and validate a graphical nomogram method for estimating free phenytoin concentration.
• To assess the accuracy of the nomogram using Scatchard binding equation and regression analysis.
• To compare predicted free phenytoin concentrations with measured values in outpatients.

Main Methods:

• Application of the graphical nomogram method based on the Scatchard binding equation.
• Calculation of binding parameters (N and Kapp) using non-linear least-squares regression analysis.
• Measurement of free phenytoin concentration using the Amicon multi-micro ultrafiltration system in 96 outpatients.

Main Results:

• The binding parameters were determined as N = 1.03 and Kapp = 18,500 M⁻¹.
• A very good correlation (r = 0.94) was observed between measured and predicted free phenytoin concentrations.
• Prediction-error analysis indicated a slight overprediction of measured free phenytoin (PHT) concentration by approximately 10% (15-30 mg/l).

Conclusions:

• The graphical nomogram method provides a reliable tool for estimating free phenytoin concentrations.
• The method demonstrates good predictive accuracy, though a slight overprediction warrants consideration in clinical application.
• Further validation in diverse patient populations may enhance the nomogram's utility in routine clinical practice.