Comparative bioavailaibilty of two valproic acid delayed-release tablets in healthy volunteers with tighter acceptance criteria to anticipate breakthrough seizures

The present study was performed to investigate if the generic of valproic acid delayed release is interchangeable on the basis bioequivalence to the reference product. Due to previous report of breakthrough seizures following a change from a brand name product to a generic product, this bioequivalence study was conducted using tightened acceptance criteria for assuring the therapeutic equivalence. Twenty eight healthy volunteers participated in an open-label, randomized and two-way crossover study under fasting conditions. Plasma samples were collected up 72 hours following drug administration and were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters used for bioequivalence assessment were AUC_0-t, AUC_0-∞, and C_max. The 90% CI bioequivalence limits was tightened from the traditional 80.00% -125.00% to 90.00%-111.11%. All volunteers completed the study. The 90% confidence intervals obtained by analysis of variance for AUC_0-t, AUC_0-∞, and C_max were 98.38%-104.61%, 98.93%-105.31%, and 92.62%-102.93%, respectively. Both formulations were tolerated and no serious adverse events were reported. These results were all within the range of 90.00-111.11%. The low intra-subject variability observed in this study indicates that tightened acceptance criteria are still applicable for valproic acid BE study.