Therapeutic monitoring of antiepileptic drugs

Abstract

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) has made it possible to reveal non-compliance in patients, to study the individual variations in drug utilization occurring normally, or as a consequence of disease or otherwise altered physiologic states and for quality assurance aspects. Older AEDs, like phenytoin, carbamazepine and valproic acid, have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined "therapeutic range," representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution since many patients are optimally treated when they have serum concentrations below or above the suggested range. Now, several new AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide) are available. For all AEDs, it would be more appropriate to focus on the concept of "individualized reference concentrations" rather than "therapeutic ranges", aiming at identifying the optimal concentration at which each patient shows the best response. The pharmacokinetic variability is less pronounced for the new AEDs that are eliminated completely (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate) through the kidneys. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Comedication can affect drug concentration markedly for AEDs that are metabolized, and individual factors such as age, pregnancy, and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For the new AEDs that are cleared by metabolism (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide) pharmacokinetic variability is just as relevant as for many of the traditional AEDs. TDM is therefore likely to be useful in many clinical settings also with the arrival of the new generation AEDs. In addition, many AEDs are now also used for non-epilepsy disorders, like bipolar disorder, neuropathic pain and migraine, with a potential benefit of TDM.