Simulation study of the relationship between variation in bioavailability and clinical equivalence using a direct link model.

OBJECTIVE

The aim of this study was to investigate whether the bioequivalence range applied world-wide, 80-120%, ensures the clinical equivalence. We investigated the relationship between variations of AUC and Cmax and those of AUEC based on a direct link model using a simulation technique.

METHODS

A one-compartment pharmacokinetic model and a sigmoid Emax pharmacodynamic model were used. Regarding the influence of AUC variation on AUEC variation, the total clearance value was changed from 80% to 120%. Regarding the influence of Cmax variation on AUEC variation, Cmax was changed from 80% to 120% under a constant AUC value estimated from zero to four elimination half-lives of a drug.

RESULTS

In the case that Y, shape factor, is less than 1, irrespective of the ratio of EC50 to Cmax, AUEC is within the acceptable range as long as AUC and Cmax are within the acceptable range for bioequivalence, BE. In the case that Y is more than 1, and Cmax is lower than EC50, AUEC may fail within the acceptable range in the case that AUC and Cmax are within the acceptable range for BE.

CONCLUSION

These results suggest that 20% difference for BE does not always ensure the clinical equivalence for all drugs.