Comparative in vitro and in vivo evaluation of three tablet formulations of amiodarone in healthy subjects

BACKGROUND AND THE PURPOSE OF THE STUDY The relative in vivo bioavailability and in vitro dissolution studies of three chemically equivalent amiodarone generic products in healthy volunteers was evaluated in three separate occasions. The possibility of a correlation between in vitro and in vivo performances of these tablet formulations was also evaluated. METHODS The bioequivalence studies were conducted based on a single dose, two-sequence, cross over randomized design. The bioavailability was compared using AUC(0-72), AUC(0-8), C(max) and T(max). Similarity factor, dissolution efficiency (DE), and mean dissolution time (MDT) was used to compare the dissolution profiles. Polynomial linear correlation models were tested using either MDT vs mean residence time (MRT) or fraction of the drug dissolved (FRD) vs fraction of the drug absorbed (FRA). RESULTS Significant differences were found in the dissolution performances of the tested formulations and therefore they were included in the development of the correlation. The 90% confidence intervals of the log-transformed AUC0-72, AUC(0-8), and C(max) of each two formulations in each bioequivalence studies were within the acceptable range of 80-125%. Differences were not observed between the untransformed T(max) values. Poor correlation was found between MRT and MDT of the products. A point-to-point correlation which is essential for a reliable correlation was not obtained between pooled FRD and FRA. The dissolution condition which was used for amiodarone tablets failed for formulations which were bioequivalent in vivo and significant difference between the dissolution characteristics of products (f2<50) did not reflect their in vivo properties. MAJOR CONCLUSIONS Bioequivalence studies should be considered as the only acceptable way to ensure the interchangeability and in vivo equivalence of amiodarone generic drug products. The dissolution conditions used of the present study could be used for routine and in-process quality control of amiodarone tablet formulations.