Abstracts

RATIONALE: The objective of the fasting study was to investigate the individual bioequivalence of Bertek[ssquote]s 300 mg extended phenytoin sodium capsule (Phenytek[tm]) to three Parke-Davis[ssquote] 100 mg Dilantin[reg]Kapseals[reg] following administration of a single, 300 mg oral dose in healthy volunteers.
Extended phenytoin sodium 300 mg is the most commonly prescribed daily dose for seizure patients. While phenytoin sodium has been available since 1938, no single, extended phenytoin sodium 300 mg dosage unit is available. The current study demonstrated individual bioequivalence between a new 300 mg extended phenytoin sodium capsule, Phenytek[tm] (Bertek) to 3 x 100 mg Dilantin[reg]Kapseals[reg].
METHODS: The study utilized single-dose, four-period, two-treatment, replicate, and crossover design. After a supervised overnight fast of at least 10 hours, each subject received either a single, oral 300 mg (1 x 300 mg) dose of Bertek[ssquote]s extended phenytoin sodium capsules (Phenytek[tm]) or 3 x 100 mg Parke-Davis[ssquote] Dilantin[reg]Kapseals[reg] with 240 mL of water in this study. A three-week washout separated each period. Serial blood samples, 10 mL (1 x 10 mL), were collected at predose and at 0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 8.0, 12, 16, 24, 36, 48, 72 and 96 hours post-dose. Plasma samples were stored in suitably labeled tubes at -70[degree]C [plusminus] 15[degree]C until analysis. The assay was linear from 0.050 [mu]g/mL to 10.00 [mu]g/mL. The method developed for the analysis of phenytoin in human plasma (heparin) was performed using high performance liquid chromatography with ultraviolet detection, which had a limit of quantification of 0.050 [mu]g/mL. The between-day precision of the assay was 5.8% or less. The between-day accuracy varied within -1.4% and 1.4% of the nominal concentration. Single-dose pharmacokinetic parameters for phenytoin were calculated using noncompartmental techniques. The individual bioequivalence criterion described in the FDA Guidance, entitled [dsquote]Statistical approaches to establish bioequivalence[dsquote] was used to calculate a 95% upper confidence bound for a linearized form of individual bioequivalence. Both reference-scaled method and constant-scaled method were used.
RESULTS: Twenty-four subjects completed the study . The corresponding ratio of means (Phenytek[tm]/ Dilantin[reg]Kapseals[reg]) for AUCL, AUCI, and CPEAK were 105.27%, 104.64%, and 106.90%.
For all pharmacokinetic metrics in this study, the within-subject variability was low (CV less than 12%). For all three metrics (AUCl, AUCI ans CPEAK), the within-subject variabilities of the test and reference products were very similar. In fact the Phenytek[tm] variability was smaller than that for Dilantin[reg]Kapseals[reg]. The subject-by-formulation interaction was very small for all metrics, except possibly for CPEAK.
CONCLUSIONS: Since the within-subject standard deviations are less than 0.2, the applicable criterion is the constant scaled. All metrics pass individual bioequivalence criterion. Phenytek[tm] (300mg) is individual bioequivalent to Dilantin[reg]Kapseals[reg] (3 x 100 mg).
[Supported by: Mylan Pharmaceuticals Inc. and Bertek Pharmaceuticals Inc.]; (Disclosure: Salary - Mylan, Stock - Mylan)