Variability in the Bioavailability of Phenytoin Capsules in Males and Females
- 124 Downloads
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.
Unable to display preview. Download preview PDF.
- 1.FDA. BA and BE Studies for Orally Administered Drug Products-General Considerations. Draft Guidance for Industry, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville, MD, August 1999.Google Scholar
- 2.FDA. Phenytoin/Phenytoin Sodium (capsules, tablets, suspension) In Vivo Bioequivalence and In Vitro Dissolution Testing. Guidance for Industry, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville, MD, March 1994.Google Scholar
- 3.M. Gibaldi and D. Perrier. Pharmacokinetics, Marcel Dekker, New York, 1975.Google Scholar
- 4.D. J. Schuirmann. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokin. Biopharm. 15:657-680 (1987).Google Scholar
- 5.FDA. Average, Population, and Individual Bioequivalence Approaches to Establishing Bioequivalence. Draft Guidance for Industry, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville, MD, August, 1999.Google Scholar
- 6.V. M. Chinchilli. The assessment of individual and population bioequivalence. J. Pharmacokinet. Biopharm. 6:1-14 (1996).Google Scholar
- 7.V. M. Chinchilli and J. D. Esinhart. Design and analysis of intra-subject variability in cross-over experiments. Stat. Med. 15:1619-1634 (1996).Google Scholar
- 8.G. Howe. Approximate confidence limits on the mean of X+Y where X and Y are two-tabled independent random variables. J. Amer. Stat. Assoc. 69:789-794 (1974).Google Scholar
- 9.N. Ting, R. K. Burdick, F. A. Graybill, S. Jeyaratnam, and T. F. C. Lu. Confidence intervals on linear combinations of variance components that are unrestricted in sign. J. Stat. Comp. Sim. 35:135-143 (1990).Google Scholar
- 10.T. Hyslop, F. Hsuan, and D. J. Holder. A small-sample confidence interval approach to assess individual bioequivalence. Stat. Med. in press.Google Scholar
- 11.K. Mamiya, I. Ieiri, J. Shimamoto, E. Yukawa, J. Imai, H. Ninomiya, H. Yamada, K. Otsubo, S. Higuchi, and N. Tashiro. Epilepsia 39:1317-1323 (1998).Google Scholar
- 12.G. Shavit, P. Lerman, A. D. Korczyn, M. Bechar and S. Gitter. Phenytoin pharmacokinetics in catamenial epilepsy. Neurology 34:959-961 (1984).Google Scholar
- 13.N. Kumar, M. Behari, G. K. Ahuja and B. L. Jaikhani. Phenytoin levels in catamenial epilepsy. Epilepsia 292:155-158 (1988).Google Scholar