Assessing pharmacokinetic and pharmacodynamic interactions in clinical trials of antiepileptic drugs.

An understanding of the pharmacokinetic and pharmacodynamic properties of a drug is a basic requirement for its clinical use. The investigations of these properties and their timing are fairly clearly defined in the drug development process. Without fundamental knowledge of the pharmacokinetics and pharmacodynamics of a drug, a physician could not use it appropriately, nor would a regulatory agency be likely to approve its use. Information about the interactions of a new antiepileptic drug with other antiepileptic drugs also aids a physician and is required, in varying degrees, by regulatory agencies. The amount of this information that is needed depends, in part, on the class of drug and the population for which the agent is intended. Because antiepileptic drugs are often used as polytherapy and generally are developed first for this use, their interaction potential must be part of the thought process in their development. The correct time to obtain this information, however, is not clearly defined. The analytic methodology to investigate the pharmacokinetic profile of an NCE exists and is fairly sophisticated. This methodology has enabled the development of study designs to investigate pharmacokinetic interactions. Because the plasma concentration of an antiepileptic drug may be increased or decreased as a result of pharmacokinetic interactions with concomitant antiepileptic drugs, it is of great importance to know about the specific interaction potential of an antiepileptic drug early in its development. Recent studies have confirmed the importance of investigating pharmacokinetic interactions in phase I before proceeding into phases II and III. Without this information, study results are often difficult to interpret; with this knowledge, study designs can be modified to minimize the confounding effect. A methodology exists to investigate the pharmacodynamic effects of an antiepileptic drug at receptors in cell cultures and in animal models of seizures; however, no procedure has been established to evaluate the short-term or immediate clinical pharmacodynamic effect of an antiepileptic drug, as has been done for other classes of drugs and other diseases. The clinical effect that is sought in trials with antiepileptic drugs is a reduction in seizures with little toxicity. The methodology to investigate the effect of seizure reduction over time has been used repeatedly with minor variations in the development of all the new antiepileptic drugs. However, no study has evaluated the effect of pharmacodynamic interactions among antiepileptic drugs on seizure reduction. Some studies have purported to show an interaction effect on adverse events, and assumptions are made about pharmacodynamic interactions. Although the information regarding pharmacodynamic interactions is important and existing trial designs could evaluate this, there has been no perceived need to carry out such trials. This information is less accessible than pharmacokinetic interaction information. Moreover, pharmacodynamic interactions, as opposed to pharmacokinetic interactions, are probably unidirectional and lead only to increased effects. Although it would be preferable to have this knowledge, an antiepileptic drug can be used effectively without it; over time, the information about pharmacodynamics will be inferred. Thus, conducting pharmacokinetic interaction studies with antiepileptic drugs early in their development as part of phase I is essential, whereas obtaining pharmacodynamic interaction information can be deferred.