Suitability of Various Noninfinity Area Under the Plasma Concentration–Time Curve (AUC) Estimates for Use in Bioequivalence Determinations: Relationship to AUC from Zero to Time Infinity (AUCO–INF)

Abstract

The influence of random error and elimination rate on estimates of the area under the curve from zero to time infinity (AUC0–INF) was determined in a simulation study using noninfinity measured AUC values (i.e., AUCTM, area to a measured common sampling time, and AUC0-LAST, area to the last measured sampling time). Further, the extent of absorption of generic danazol, baclofen, and oxazepam was determined using measured methods of estimating area under the curve in bioequivalence studies. The noninfinity AUC estimates and their 90% confidence intervals for the difference in product means were compared for each individual drug. Products chosen fulfilled one of the following three criteria: (1) a high “apparent intrasubject variability” and a half-life greater than 8 hr (danazol); (2) a low apparent intrasubject variability and a half-life less than 4 hr (baclofen); and (3) products exhibiting a low apparent intrasubject variability and a half-life greater than 8 hr (oxazepam). For the simulated data, AUCTM performed best when subjects had similar half-lives (i.e., low variability), which results in AUCTM = AUC0–LAST. On the other hand, AUC0–LAST worked best with a high fractional standard deviation (fsd) and a short elimination half-life (i.e., less than 4 hr). The noninfinity 90% confidence intervals for danazol and oxazepam were inconsistent with those observed at AUC0–INF. However, baclofen, which has a short elimination half-life, exhibited good agreement between the noninfinity and the AUC0–INF 90% confidence intervals. However, across all three drug groups, the comparison based upon the area calculated from time zero to the last quantifiable concentration, AUC0–LAST, consistently provided the best approximation of AUC0–INF.