Bioequivalence study of two limaprost alfadex 5 µg tablets in healthy subjects: moisture-resistant tablet (dextran formulation) versus standard tablet (lactose formulation)

Objective: A study was conducted to assess the bioequivalence of two limaprost alfadex 5 μg tablets, a moisture-resistant tablet (dextran formulation) and a standard tablet (lactose formulation). Materials and methods: The clinical investigation was designed as a randomized, open-labeled, two-part, two-treatment, two-period crossover study, in 120 healthy male volunteers. One tablet of either formulation was administered with 200 ml of water after 10-hour overnight fast. After dosing, serial blood samples were collected for a period of 6 hours. Plasma harvested from blood was analyzed for limaprost by a validated LC/MS/MS method. The peak plasma concentration (C max ) values and time associated with the maximal concentration (t max ) were obtained from the observed data. The elimination rate constant (λz) was obtained as the slope of the linear regression of the log-transformed concentration values vs. time data in the terminal phase, and the elimination half-life (t 1/2 ) was calculated as 0.693/λz. The area under the curve to the last measurable point (AUC 0-t ) was estimated by the linear trapezoidal rule. The analysis of variance (ANOVA) was carried out using log-transformed AUC 0-t , AUC 0-∞ and C max and untransformed t max , and 90% confidence intervals for AUC 0-t and C max were calculated. If the 90% confidence intervals (CI) for both AUC 0-t and C max fell fully within the interval 80 - 125%, the bioequivalence of the two formulations was established. Results: The means of AUC 0-t were 0.779 vs. 0.754 pg × h/ml (test vs. reference), and the means of the C max were 1.26 vs. 1.12 pg/ml (test vs. reference). The geometric mean ratios of the test formulation to reference formulation for AUC 0-t and C max were 104.0 and 112.4%, respectively, and the 90% Cl for AUC 0-t and C max were 100.7- 107.4% and 105.6 - 119.6%, respectively. Both 90% Cl for AUC 0-t and C max fell within the Ministry of Health, Labour and Welfare of Japan accepted bioequivalence range of 80 - 125%. Conclusions: Based on the results, the moisture-resistant tablet was determined to be bioequivalent to the standard tablet.