Evidence-Based Implementation of Free Phenytoin Therapeutic Drug Monitoring (Drug Monitoring and Toxicology) (Clinical Report‪)‬

There is increasing interest in measuring free drug concentrations for a variety of substances, based on the principle that the free drug is the pharmacologically active component (1). This is particularly true for phenytoin, which is highly bound to plasma protein (~90%), producing a very small free fraction. The common laboratory practice is to measure total phenytoin concentrations, which assumes that phenytoin protein binding is relatively constant, so that the concentration of the active unbound drug can be predicted from the total drug plasma concentration (2,3). Despite the high percentage of protein binding, there can be substantial interindividual variation in free phenytoin concentrations, ranging from 9% to 25% (4). The free drug fraction of phenytoin can be altered by various compounds and clinical situations, including hypoalbuminemia (5), uremia (6), pregnancy (7), critical illness (8), HIV infection (9), and administration of other drugs, including antiepileptic drugs (4,10,11). The potential for clinically significant discordance between free and total phenytoin concentrations exists for the above reasons. Several studies have addressed the correlation between total and free phenytoin (12,13), with earlier studies supporting a strong correlation between total and free phenytoin (4,14) and more recent studies advocating free drug measurements (1,10,13 ). Kilpatrick et al. (13) examined the association between free phenytoin and clinical status and found that in all patients the unbound concentration of phenytoin reflected the clinical status equally or better than the total phenytoin concentration.