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Summary:This article reexamines the role of blood-level monitoring (therapeutic drug monitoring, TDM) of antiepileptic drugs (AEDs) in the current treatment of epilepsy and identifies situations in which TDM can be useful. Basic pharmacokinetic and pharmacodynamic principles are reviewed, with spccific emphasis on kinetics of absorption/distribution/ metabolism, elimination half-life, time to steady state, and plasma drug concentrations. The relationship between AED intensity of effect (pharmacodynamics) and plasma concentration (pharmacokinetics) is expressed mathematically, examined in the context of the major old and new AEDs, and integrated with a historical look at the role of TDM. Situations in which TDM can be useful in the modern treatment of epilepsy are presented and discussed. For both older and ncwer AEDs, TDM is useful in six clinical situations: establishing "baseline" effective concentrations, evaluating potential causes for lack of efficacy, evaluating potential causes for toxicity, evaluating potential causes for loss of efficacy, judging "room to move" or when to change AEDs, and minimizing predictable problems. TDM remains a valuable tool in the modern treatment of epilepsy. It can be selectively and appropriately utilized to help maximize seizure control and minimize side effects if levels arc obtained in response to a patient-specific pharmacokinctic or pharmacodynamic issue or problem Key Words: EpilepsyTherapeutic drug m o n i tori n g-P h ar m a c o k i n e t i c sPharmacodynamics-Antiepileptic drugsThe goal of antiepileptic drug (AED) therapy for people with epilepsy is seizure freedom without side effects.l'2 Even with the advent of new AEDs, a significant number of people with epilepsy still cannot achieve this goal.'34 There are a number of reasons for this predicament, including, among others, misdiagnosis of seizure type and subsequent incorrect AED selection, interpatient variations in dose-response and AED tolerability, variable levels of compliance with prescribed regimens, and flawed approaches to adjusting medication^.^.^ If used improperly (e.g., misinterpretation), AED blood level monitoring (therapeutic drug monitoring, TDM) can aggravate these problems. 738 We propose that TDM of AEDs is still important in the modern treatment of epilepsy. Clinicians should treat the patient, not the blood but blood-level monitoring can be selectively and appropriately utilized to help maximize seizure control and minimize side effects

The relationship between free radicals and scavenger enzymes, and the disorders called the neuronal ceroid-lipofuscinoses, has long been an argumentative one. Recent evidence would seem to support the fact that such a relationship might exist but that it is indirect. The relationship does not seem due to an inborn error of free radical scavenger enzyme metabolism. Anticonvulsants play a role, as they influence free radical generating systems. At this juncture, no one has studied the relationship of anticonvulsant therapy, neuronal ceroid-lipofuscinosis, and the free radical-scavenging enzyme system, and their interplay. We have studied a large number of patients with epilepsy who are on either monotherapeutic or polytherapeutic regimens of most of the common anticonvulsants. We have found excessive free radical production in many of these patients, ranging from minor effects in the simpler anticonvulsants when used monotherapeutically, to more complex changes in polytherapeutic combinations. Likewise, we have found subtle and inconsistent findings in the free radical-scavenging enzyme system in a variety of examples of neuronal ceroid-lipofuscinosis. When refractory seizure disorders stimulate the vigorous use of polytherapy with a variety of free radical-facilitating anticonvulsants, free radical production becomes deleterious. Likewise, in certain types of neuronal ceroid-lipofuscinosis, polypharmacy with anticonvulsants, by enhancing the production of free radicals or suppressing scavenging enzymes, tends to be deleterious and induces a worsening in the disease process.

Specific oxidative metabolites of valproic acid (VPA) have been associated with the clinically defined toxicity of the drug. To investigate the role of enzymatic detoxification in clinical toxicity, we compared activities of five antioxidant enzymes in 15 patients with a serious adverse experience (SAE) related to VPA therapy, to enzyme activities measured in 35 patients with good clinical tolerance of VPA, and 50 healthy, age-matched subjects. These enzymes included glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glutathione transferase, superoxide dismutase, and catalase in erythrocytes; and GSH-Px in plasma. We also determined levels of Se, Cu, and Zn, trace elemental cofactors for these enzymes, in plasma from each individual. In patients with a VPA-associated SAE, GSH-Px was significantly depressed and GSSG-R was significantly elevated relative to values for the other groups. Selenium and zinc concentrations were lower in SAE patients than in controls. These findings may indicate a role for selenium dependent antioxidant activity in individual susceptibility to an SAE related to VPA therapy.

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