Multiple-Dose Studies can be a More Sensitive Assessment for Bioequivalence than Single-Dose Studies : The Case with Omeprazole.

OBJECTIVE

To evaluate the bioequivalence of two enteric-coated formulations of omeprazole, Losec® (reference) and Omepradex® (test). It is hypothesised that formulation differences may be accentuated following multiple-dose administration, and that testing after multiple administration may therefore provide a more sensitive assessment of bioequivalence.

STUDY PARTICIPANTS AND DESIGN

The study comprised two parts: an in vitro dissolution test and an in vivo bioavailability study. The latter was a randomised, two-way crossover comparative study after a single dose and after multiple doses in healthy volunteers. Forty subjects were randomly allocated to receive either test or reference product, once daily in the morning, and blood samples were taken on days 1 and 5. Standard pharmacokinetic analyses were performed, and analysis of variance (ANOVA) was used to compare the log-transformed variables in a model including terms for treatment, subject and period.

RESULTS

Although both products meet the formal requirements specified by the United States Pharmacopoeia (USP) for enteric-coated articles, the in vitro dissolution experiments revealed widely differing properties for the two tested products. Less than 10% of the drug content was recovered from the Omepradex® formulation following a pre-exposure to pH 3 or 4, compared with over 90% recovered from the Losec® formulation. These findings were in agreement with the results of the in vivo bioavailability study, which showed that the two products differed in both their rate and extent of absorption after a single dose and following multiple doses. The products failed the bioequivalence test for area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (C) after a single dose [AUC: test/reference ratio 0.85, 90% confidence interval (0.76-0.95); C: test/reference ratio 0.85, 90% confidence interval (0.75-0.95)], and the difference between the formulations was even more pronounced after multiple doses [AUC: test/reference ratio 0.73, 90% confidence interval (0.65-0.83); Cmax: test/reference ratio 0.71, 90% confidence interval (0.63-0.81)].

CONCLUSIONS

These data suggest that bioequivalence studies on enteric-coated proton pump inhibitors should include both single- and multiple-dose elements to be fully decisive. The two omeprazole products failed to show bioequivalence, with the observed differences being even more apparent after multiple doses, as postulated. Based on this study, the two products may not be considered either therapeutically equivalent or interchangeable.