Comparison of average, scaled average, and population bioequivalence methods for assessment of highly variable drugs: An experience with doxifluridine in beagle dogs

Several strategies for overcoming the challenge of establishing bioequivalence (BE) for highly variable drugs (HVDs; drugs having within-subject variability >0.3) have been considered in recent years. Within-subject variability of the area under the curve (AUC4 h) and peak concentration (Cmax) of doxifluridine in the minimal group (n = 24) were 0.444 and 0.491, respectively, meeting the criteria for an HVD. For the large group (n = 60), within-subject variability of the AUC4 h and Cmax were 0.431 and 0.493, respectively. The 90% confidence interval for the AUC4 h and Cmax of the ratio of the test drug to the reference drug exceeded the acceptable BE limits (0.80–1.25) of the ABE (average bioequivalence), in both the minimal and large groups. However, the 90% CI fell within the extended BE limits (0.61–1.64) of the SABE (scaled average bioequivalence), calculated using within-subject variability. The 95% CI of the AUC4 h and Cmax of the ratio of test to reference drug were within the extended BE limit (<1.73) of the PBE (population bioequivalence), calculated using total variance. Our results suggest that the SABE method may be useful for evaluating the BE of HVDs and for meeting the need for international guidelines for BE.