Clinical decision support of therapeutic drug monitoring of phenytoin: measured versus adjusted phenytoin plasma concentrations

Matthew D Krasowski,Louis E Penrod

doi:10.1186/1472-6947-12-7

Abstract

BackgroundTherapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. This is most commonly accomplished by measurement of total phenytoin plasma concentrations. However, total phenytoin levels can be misleading in patients with factors such as low plasma albumin that alter the free (unbound) concentrations of phenytoin. Direct measurement of free phenytoin concentrations in plasma is more costly and time-consuming than determination of total phenytoin concentrations. An alternative to direct measurement of free phenytoin concentrations is use of the Sheiner-Tozer equation to calculate an adjusted phenytoin that corrects for the plasma albumin concentration. Innovative medical informatics tools to identify patients who would benefit from adjusted phenytoin calculations or from laboratory measurement of free phenytoin are needed to improve safety and efficacy of phenytoin pharmacotherapy. The electronic medical record for an academic medical center was searched for the time period from August 1, 1996 to November 30, 2010 for patients who had total phenytoin and free phenytoin determined on the same blood draw, and also a plasma albumin measurement within 7 days of the phenytoin measurements. The measured free phenytoin plasma concentration was used as the gold standard.ResultsIn this study, the standard Sheiner-Tozer formula for calculating an estimated (adjusted) phenytoin level more frequently underestimates than overestimates the measured free phenytoin relative to the respective therapeutic ranges. Adjusted phenytoin concentrations provided superior classification of patients than total phenytoin measurements, particularly at low albumin concentrations. Albumin plasma concentrations up to 7 days prior to total phenytoin measurements can be used for adjusted phenytoin concentrations.ConclusionsThe results suggest that a measured free phenytoin should be obtained where possible to guide phenytoin dosing. If this is not feasible, then an adjusted phenytoin can supplement a total phenytoin concentration, particularly for patients with low plasma albumin.

Highlights

Therapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects
To substantially improve the quality of care, the Institute of Medicine (IOM) has called for computerized physician order entry (CPOE) coupled with clinical decision support systems (DSS) [2]
There were a total of 1,753 datapoints from 756 patients that had simultaneous determination of PHTtotal and PHTfree and a plasma albumin measured within 7 days of the PHT measurements

Summary

Introduction

Therapeutic drug monitoring of phenytoin by measurement of plasma concentrations is often employed to optimize clinical efficacy while avoiding adverse effects. To substantially improve the quality of care, the IOM has called for computerized physician order entry (CPOE) coupled with clinical decision support systems (DSS) [2] Such a combination has been shown to reduce medical errors [3] and speed adoption of new patterns of practice [4] as prime. PHT dosing is challenging because the drug exhibits non-linear pharmacokinetics, zero-order elimination, and a multitude of drug-drug interactions [8,9,10,11] For this reason, drug levels are measured to optimize dosing, with the usual therapeutic range for plasma total PHT concentration (PHTtotal) considered to be 10-20 mg/L [12]. The therapeutic range for free PHT plasma concentrations (PHTfree) is generally considered to be 1-2 mg/L (i.e., PHTtotal divided by 10 or PHTtotal/10), using an estimated 10% free fraction of PHT [12]

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