Experimental, extrapolated and truncated areas under the concentration-time curve in bioequivalence trials

The extrapolated area under the concentration-time curve (AUC0-infinity) for any drug is considered by operating guidelines as the primary parameter related to the extent of absorption in single-dose bioavailability and bioequivalence trials. Not more than 20% should be added to the experimental AUC (AUC0-t) in the extrapolating procedure. However, in certain specific cases, it is problematic and, in other cases, impossible to respect the above requirement. It was intended to demonstrate that truncated AUC or AUC0-t would be used in bioequivalence trials when the AUC cannot be extrapolated.

AUC0-t and truncated AUC were compared at various time intervals with AUC0-infinity in a series of 19 single-dose bioequivalence trials covering 15 different drugs, each carried out on 12-24 healthy volunteers. Point estimators and 90% confidence intervals in the 0.80-1.25 and 0.70-1.43 ranges were statistically processed using log-transformed parameters.

In all the trials considered, overlapping point estimators and 90% confidence intervals were invariably obtained, regardless of the AUC used.

The use of AUC0-t or truncated AUC may be considered an ancillary procedure in bioequivalence trials when AUC cannot be extrapolated. This occurs with most extended-release formulations, endogenous substances, and poorly absorbed drugs. It also occurs in trials with one or more poor metabolisers, with drugs possessing very long elimination half-lives, and with bioassays having problems of sensitivity that preclude sufficiently precise plasma concentration measurement over the required sampling period.