The Clinical Epilepsy Section continues to study the clinical pharmacology of old and new antiepileptic drugs. In a study of a relatively old drug, the pharmacokinetics of phenytoin were studied, especially its saturable metabolism; a new observation, the pseudo-steady-state phenomenon was described, which aids in an understanding of the difficulties that physicians often have in utilizing this drug for effective, nontoxic care of their patients. In this model, a dosage adjustment may initially lead to rapid fluctuations in plasma drug levels because of changes in various body compartments, followed by a flattening of the plasma drug level curve as tissue and blood concentrations equilibrate. Subsequent changes in plasma drug levels occur as a result of distribution into and out of poorly diffused tissue. In another study of phenytoin, the rationale for studying free, rather than total phenytoin levels was investigated. The importance of establishing the role of free phenytoin determinations was important because some authors have suggested that free phenytoin levels correlate more closely than total levels with seizure control. In our study, free phenytoin measurements were only marginally better predictors of either drug toxicity or drug efficacy, allowing us to conclude that routine monitoring of such free levels is not warranted. New studies are planned with a promising dicarbamate, W-554. This compound, which has activity against maximal electroshock in rodents, will be studied in patients with uncontrolled partial seizures; the study will be a randomized, double blind, placebo-controlled study performed in the Clinical Center, NIH. Pilot studies at other institutions suggest that the drug may be very effective. All pharmacologic evaluations of antiepileptic drugs are coupled with efficacy studies, carried out by intensive monitoring techniques, including videotape analysis of epileptic seizures with simultaneous telemetered EEG recordings and daily determinations of antiepileptic drug levels.
