Reference-Scaled Average Bioequivalence (SABE)

• Activity Number: 673
• Type: Topic Contributed
• Date/Time: Thursday, August 8, 2013 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): L. Endrenyi*+ and Laszlo Tothfalusi
• Companies: Univ of Toronto and Semmelweis University
• Keywords: Bioequivalence ; Scaled average bioequivalence ; Highly variable drugs ; Narrow therapeutic index drugs ; Regulatory criterion

Abstract

SABE standardizes the difference between the average pharmacokinetic parameters of two drug products by the standard deviation of the reference formulation (sW). It has been adopted by major regulatory agencies, such as FDA, for determining the bioequivalence of highly-variable drug products. It enables to plan studies with reasonably few subjects. SABE generally requires replicate-design studies. However, the implementation of SABE has differed in various jurisdictions. With the regulatory parameters stated by FDA, the BE limits are discontinuous at sW=0.30. FDA imposes also a secondary criterion. This expects that the point estimates of the ratio of geometric means (GMR) of the pharmacokinetic parameters should be between 0.80 and 1.25. EMA in the European Union recommends a corresponding approach. Unscaled average BE is utilized in which the BE limits expand in proportion to sW. However, the expansion may be applied only to Cmax, using again the constraint on GMR, and only up to CV=50%. The suggested regulatory constants ensure the continuity of the BE limits. FDA has recently applied SABE also for determining the BE between some drug products with narrow therapeutic indices.