Variability in the Bioavailability of Phenytoin Capsules in Males and Females

Abstract

Purpose. To determine inter-lot and intra-subject variability in the bioavailability of the 100 mg extended phenytoin sodium capsules. In addition, to determine the effect of gender and menstrual cycle on phenytoin bioavailability.

Methods. Three different lots of extended phenytoin sodium capsules were given to 12 healthy male and 12 healthy female subjects in a crossover fashion. One of the lots was also given a second time to each subject. Plasma phenytoin was determined, using an HPLC assay, in samples collected over a 73-hr period after each dose.

Results. The mean Cmax for the four administrations ranged from 1.71-1.79 μg/ml and mean AUC(0-∞) values from ranged 53.0-54.1 μg_*hr/ml. The elimination half-life was 3 hr shorter, and the AUC(0-∞) adjusted for the mg/kg dose was 30% lower for females. Average bioequivalence was demonstrated between the three lots for both Cmax and AUC(0-∞) based on the BE limit of 80-125%. Further, all confidence intervals of AUC(0-∞) fell within the limit of 90-111%. There were no differences in the confidence limits for Cmax and AUC(0-∞) determined separately for males and females. Also, there was no difference in the mean Cmax or AUC(0-∞) for females when analyzed as a function of the week of their menstrual cycle. Individual bioequivalence was demonstrated between three lots of phenytoin using the constant-scaled method, but not the reference-scaled method.

Conclusions. There was very little difference in the bioavailability of the three lots of phenytoin. Females exhibited a lower AUC(0-∞) than males after adjustment of dose for body weight, but their inclusion in the study did not affect the assessment of bioequivalence. When dose was not adjusted for body weight, no difference in AUC(0-∞) was seen between males and females.