Assessment of 2012 Bioequivalence Standards for Warfarin

This study is a reasonable starting point to assess the appropriateness of the 2012 FDA bioequivalence (BE) statistical criteria for narrow therapeutic index drugs (NTIDs). The idea stems from an earlier study conducted in Dr. Benet's lab with the drug furosemide. The furosemide study yielded triplicate data that were unable to purely meet the BE statistical criteria set forth by the FDA due to the inherent study design. Furosemide is not an NTID to be considered by the FDA for BE studies, however. Hence, the investigators have proposed a new study to assess the BE statistical criteria with warfarin, an NTID with a draft guidance issued by the FDA. By providing the reference product (brand name warfarin) three times to each study participant and recording the relevant pharmacokinetic parameters for BE (AUC and Cmax), the investigators can make three comparisons between the data (R1 and R2 vs. R2 and R3; R1 and R2 vs. R1 and R¬3; R2 and R3 vs. R1 and R3). The investigators have three concerns that can be tested here. 1. Will normal within subject variability potentially lead to inequivalence of the reference product using the new NTID BE regulations? 2. Is it possible that the BE interval could be less than the United States Pharmacopeia (USP) content uniformity limits for warfarin? 3. Provide a comparison of the within-subject variance for the 2.5 ratio comparison.