Chiral bioequivalence - Effect of absorption rate on racemic etodolac

Background: For many racemic drugs, bioequivalence assessment based on isom er-nonspecific assays is appropriate because enantiomeric area under the co ncentration-time curve (AUC) exposure ratios are close to unity. Use of non specific methods in cases in which the ratio is substantially greater or le ss than 1, however, may obscure real therapeutic differences among formulat ions, especially if the enantiomers exhibit differing pharmacological poten cies. Objective: To examine the influence of absorption rate on etodolac bioequiv alence as measured by total [(R,S)-] and (S)-etodolac. Design: Single dose, 3-period, crossover, pharmacokinetic study in 24 healt hy volunteers in which the administration rate of etodolac was varied. Methods: Participants received etodolac 400mg in solution, given as a singl e dose over 1 minute or as divided doses over 30 and 90 minutes. Unresolved and enantiomer concentrations of etodolac were measured by a validated HPL C assay. The enantiomer ratio was similarly measured by HPLC. Results: Bioequivalence parameters derived fur both unresolved and (S)etodo lac indicate that peak plasma drug concentration (C-max) was not bioequival ent. By delaying absorption, bioequivalence was lost. Conclusions: Collectively, these data demonstrate that bioequivalence betwe en 2 products of etodolac based on enantiomerically nonspecific criteria al one may not generalise to the pharmacologically relevant (S)-enantiomer. Th is suggests that enantiospecific assays are necessary for bioequivalence as sessments.