Absorption rate vs. exposure: which is more useful for bioequivalence testing?

PURPOSE

The goals were to evaluate the usefulness of Cmax/AUClqc, ratio of the maximum plasma drug concentration to the area under the plasma concentration-time curve to the time of the last quantifiable concentration, in bioequivalence testing and to explore the use of exposure as a replacement for the concepts of rate and extent of drug absorption.

METHODS

The bioequivalence of products differing in both rate (ka) and extent (F) of absorption was assessed under conditions similar to those encountered in a typical trial. A one-compartment model drug with first-order absorption (rate constant = ka) and eliminations was used. Variability was introduced in all model parameters using Monte Carlo techniques. The results were expressed in terms of the probability of declaring bioequivalence in a cross-over trial with 24 subjects using Cmax/AUClqc, AUClqc, and Cmax as bioequivalence measures.

RESULTS

The outcome of a bioequivalence trial was shown to depend on the measure. Cmax/AUClqc reflected changes in ka, but not in F. AUClqc showed dependence on F, but virtually no dependence on ka. For Cmax, a 3- to 4-fold increase in ka and a concomittant 20% decrease in F, as well as corresponding changes in the opposite directions, resulted in bioequivalent outcomes.

CONCLUSIONS

It was concluded that use of Cmax/AUClqc should be discouraged and that defining bioequivalence in terms of rate and extent of absorption has major problems. The goal of bioequivalence trials should be to assure that the shape of the concentration-time curve of the test product is sufficiently similar to that of the reference product. To this end, the use of "exposure" rather than "rate and extent of absorption" concepts is encouraged.