Журнал биоэквивалентности и биодоступности

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Single-Dose, Randomized, Open-Label, Two-Way, Crossover Bioequivalence Studies of two formulations of 500-mg Delayed-Release Valproate semisodium Tablets in Healthy Mexican Population Under Fasted and Fed Conditions

Alberto Martínez-Muñoz, Juan Luis Gutiérrez-Velázquez, Porfirio de la Cruz-Cruz, Luis Eligio Chablé-Cen, Fabiola Esmeralda Penilla-Flores, Juan Ernesto Dávila-Romero, Héctor Manuel González-Martínez, Araceli Guadalupe Medina-Nolasco, Sandra Lara-Figueroa, Ricardo Zamora-Ramírez, José Luis Rubio-Santiago

Therapeutic adherence has a key role in the clinical improvement of a disease; the adherence pattern of Immediate- Release formulation of Valproic Acid is relatively lower due to several gastrointestinal adverse events. Therefore, these studies evaluated the bioequivalence of a new 500 mg Delayed-Release Valproate Acid Tablets in Mexican population. The test formulation (Vupelsat^®) was manufactured by Ultra Laboratorios S.A. de C.V. (Jalisco, Mexico) with batch number: DE-LPP-20016-A and expiration date March 2022 the reference formulation (Epival^®) was manufactured by Abbott Laboratories de México, S.A. de C.V. (Mexico) with batch number: 08222MC and expiration date August 2021. The studies designs were: Single-center, single-dose, open-label, two-way, crossover with a 7-day wash-out period before the next dosing. Study A was evaluated at a fasted state (at least 10 hours before dosing) and study B was evaluated at a fed state (30 minutes before dosing). The study populations (per study) were 18 healthy male and female adult (aged 18-55 years) Mexican volunteers. Blood samples were collected before and 72.00 h after dosing were evaluated by UPLC-MS/MS. The bioequivalence of the 500-mg Delayed-Release Valproate semisodium Tablets was assessed by Non-Compartmental Pharmacokinetic analysis and under local law regulation. Tolerability and safety were evaluated throughout the research. The 90% CI (C_max, AUC_0-t, and AUC0- ∞) for Valproic Acid on fed conditions were 93.8279% to 103.2660%, 88.7329% to 99.7994%, and 87.7015% to 99.1945%; whereas, on fasted conditions were 99.3441% to 105.9729%, 95.8381% to 101.5227%, and 95.4785% to 101.6214%, respectively. Despite fasted or fed condition, concentration vs. time curves were similar for the test and reference products with a difference for the pharmacokinetic parameters of C_max, AUC_0-t, and AUC_0-∞ less than 20%, results that suggested a similar behavior in vivo. Five and three adverse events were reported in study A and B, respectively; both formulations, dosing on fed or fasted state, were considered well-tolerated and safe for human use.