Monitoring of anticonvulsants

Monitoring of serum drug concentrations for anticonvulsants was proposed and pioneered by Charles Pippenger and Harvey Kupferburg in the early 1970s (1-3). These initial papers dealt with developing methods to monitor phenytoin, primidone, phenobarbital, as well as carbamazepine, using gas-liquid chromatography (GC) techniques. The rationale for these initial studies was that patients could not be managed solely by dosing anticonvulsant drugs based on milligram per kilogram of body weight. Feldman and Pippenger (4) made the observation that several patients undergoing treatment for epilepsy remained seizure free despite levels well below the "optimal therapeutic interval" established at that time. In addition, anticonvulsant drugs fit the "profile" of drugs that should be monitored in therapeutic settings because there is a well-defined relationship between blood concentration and pharmacodynamic effects but a lack of good correlation between dose and the blood concentration in a patient. It should be noted that for many anticonvulsant drugs, lack of seizure control can occur when blood concentrations are either above or below the optimum therapeutic interval. Historically, specialists in the field of epilepsy have minimized the utility of therapeutic drug monitoring (TDM). However, as the field of TDM in epilepsy has evolved, it has been established that there are specific clinical situations where it can be useful in treatment of epilepsy. These include establishing baseline effective concentrations, evaluating causes for toxicity or lack of efficacy, evaluating non-compliance versus loss of efficacy, minimization of side effects, and evaluation of serum levels when the therapeutic regimen is changed.

Since then, assays have been developed for many of the currently available anticonvulsant drugs. These include assays based on GC, high-performance liquid chromatography (HPLC), mass spectrometry, and a wide variety of immunochemical assays. For chromatographic methods (including those coupled to mass spectrometry), potential interferences come from serum components and other drugs with extraction, or co-eluting substances during chromatography. The use of antibodies to measure drug levels allows for an automated, simple analysis of drugs; however, it introduces an additional source for assay interference, because cross-reactivity of drugs (or metabolites) with similar structural epitopes must be considered.

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