The Phenytoin Trial is a Case Study of ‘Individual’ Bioequivalence *

Proposals are being made for changes in bioequivalence criteria, the so-called ‘population’ and ‘individual’ bioequivalence methodologies. The proposed criteria require assumptions that have not yet been validated, including the equality of intra-subject variances. More data are needed about the different sources of variation. This type of information was provided by a single dose, two-formulation, four-period trial of phenytoin that used a replicated design. There were no formulation effects, thus each subject provided four observations from which intra-subject variances could be estimated; the individual intra-subject variances were equal within each formulation and were uncorrelated with individual means. This was true on both original and log-transformed scales. Observations of area under the time by concentration curve and maximum observed concentration were analyzed as the total study and within each of the two replications. Bioequivalence inferences were the same for all three analyses, indicating that for this drug ‘individual’ bioequivalence is not likely to be needed.