Bioavailability of phenytoin sodium capsules available in Thailand part II : In vivo study

Abstract

Four phenytoin brands, dilantin® and three local brands (brand A, B and C) were selected for the bioavailability study. The study was carried out in 16 healthy male Thai volunteers with the average age of 21 years old. A single oral dose of 300 mg (three capsules of 100-mg) phenytoin sodium was given to subjects following an 8 hour-overnight fast. The tested drugs were given in a single-blind randomized crossover with at least 2 weeks of washout period. Venous blood samples of approximately 5 ml were drawn before medication and at 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 hours post dosing. Plasma phenytoin concentrations were determined by HPLC assay. The pharmacokinetic parameters were calculated from the plasma-concentration time curve of an innovator brand, dilantin® , by PCNONLIN program. Elimination rate constant and half-life were 0.2 h-1 and 19 h, respectively. The maximum concentration (Cmax) and time to peak (Tmax) were 1.98 μg/ml and 9.6 h, respectively. Bioavailability study was determined by comparing the area under the plasma concentration time curve (AUC), maximum plasma concentration (Cmax) and time to reach maximum plasma concentration (Tmax) by using ANOVA. The result indicated that two local brands (brand A and brand C) were not bioequivalent to the innovator in terms of Cmax and AUC(0-α) whereas Tmax was not significantly different among these 4 brands. Cmax and AUC of brand A and C were significantly higher than the innovator brand. In addition, the plasma concentration time profile of brand C was also different from other brands with the steep peak which yielded a Cmax value double that of the Cmax of the innovator. However, brand B (from Research and Development Institute, Government Pharmaceutical Organization) was bioequivalent to dilantin® after 4 tunes of product formulation adjustment. This present study demonstrated that the local products (brand A and brand C) were not bioequivalent with the innovator. Thus, the interchange from one brand to another must be performed cautiously or should be avoided, otherwise phenytoin blood levels should be monitored closely together with the clinical signs and symptoms of the patients.