Flunarizine (FLN) is a potential antiepileptic drug whose pharmacokinetic properties include a long half-life (2-7 weeks) and high interpatient variability in volume of distribution and clearance. The National Institutes of Health (NIH) is sponsoring a randomized, double-masked, multicenter, parallel-group, placebo-controlled clinical trial to demonstrate the antiepileptic activity of FLN. The design is based on the premise that plasma concentrations are more strongly related to drug response than are doses. For each patient, an estimate of the concentration-time curve following a single dose of FLN is used to determine a loading dose and maintenance dosage targeted at a specified plasma FLN concentration. After an inpatient, drug-loading period, the fixed maintenance dosage (of FLN or placebo) is prescribed for the entire 24-week outpatient treatment period unless a change is required for medical reasons. If the target concentration is well chosen and approximately achieved, this design has several potential advantages: (a) A fixed-dose design is simpler and less subject to bias than a design involving dosage adjustments; (b) the drug-loading period reduces from several weeks or months to 1 week the time required to achieve the target plasma FLN concentration; (c) compared with a design in which each patient receives the same dose, the decreased variability in FLN concentrations should result in fewer patients receiving subtherapeutic doses and fewer patients requiring dose reductions, as well as increased power to detect treatment effects in a population where such effects are generally small.