Therapeutic Drug Monitoring of Antiepileptic Medications

Medications used to treat and prevent seizures (antiepileptic medications, AEMs) have been commonly managed by therapeutic drug monitoring (TDM) to optimize efficacy and avoid toxicity (Neels et al., 2004; Patsalos et al., 2008). TDM has been applied mostly to the firstgeneration AEMs that have been used clinically in the United States and Europe for several decades, namely carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid. First-generation AEMs generally have significant inter-individual variability in their pharmacokinetics (absorption, distribution, metabolism, and excretion) and low therapeutic indices. Two randomized, controlled studies of AEM TDM showed that practitioners often apply information from TDM incorrectly (Fröscher et al., 1981; Januzzi et al., 2000). Consequently, improved education of medical practitioners on TDM is important for the future. In the last twenty-five years, 14 new AEMs have entered the market in the United States and/or Europe (LaRoche & Helmers, 2004a,b; Patsalos, 1999). These drugs are sometimes characterized as secondor third-generation AEMs and include the following drugs: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. Eslicarbazepine acetate, lacosamide, rufinamide, and stiripentol have not yet been approved in the United States. In contrast to the first-generation AEMs, the newer agents generally (although not always) have wider therapeutic ranges and less adverse effects. This chapter focuses on TDM of AEMs in treatment of epilepsy, emphasizing whether the pharmacokinetics and clinical profile of the drug make TDM useful. AEMs are sometimes used to treat disorders other than epilepsy such as trigeminal neuralgia, fibromyalgia, and migraine headaches (Johannessen Landmark, 2008; LaRoche & Helmers, 2004a). There are several main challenges in TDM of AEMs (Patsalos et al., 2008). First, there are no simple diagnostic or laboratory tests for seizure disorders. The electroencephalogram (EEG) is useful for diagnosis of seizure disorders but is too labor-intensive for long-term patient observation. Second, seizures often occur unpredictably, sometimes with long periods of time between episodes. Lastly, the toxicity of AEMs can resemble neurologic disease, sometimes leading to inappropriate escalations of medication therapy even when the dose is actually too high. One of the most basic assumptions of TDM is that the concentration of drug being measured correlates with the concentration at the target site of action (e.g., brain tissue). TDM of AEMs