title: Estimating product bioequivalence for highly variable veterinary drugs.
abstract: The occurrence of drugs and drug formulations associated with large intrasubject pharmacokinetic (PK) variability has been well described in humans and is likewise encountered in veterinary medicine. The scaled average bioequivalence (SABE) approach adopted by CDER of the FDA for the determination of bioequivalence (BE) of highly variable drugs (HVD) needs to be considered when applied to veterinary dosage forms. However, because of some of the unique challenges that are encountered within the framework of veterinary medicine, variations of CDER's approach are presented. The present manuscript discusses HVD and highly variable veterinary drugs (HVVD) from the perspective of possible alternative approaches to support the assessment of product BE in veterinary medicine. Limitations in the use of 3- and 4-way crossover study designs are enumerated. In addition to a need for a statistical analysis of HVVD when using a parallel study design, the use of the secondary criteria (test-to-reference ratio), definition of σ(0) , and average BE with expanding limits are raised. A number of the details need to be finalized, from the selection of a regulatory constant to the determination of 'highly variable' in a veterinary drug product. Academicians, industrial scientists, and regulators should continue this discussion and resolve these details.
authors.affiliation: Schafer Veterinary Consultants, Fort Collins, CO, USA.
authors.forename: R
authors.initials: R
authors.lastname: Claxton
authors.forename: J
authors.initials: J
authors.lastname: Cook
authors.forename: L
authors.initials: L
authors.lastname: Endrenyi
authors.forename: A
authors.initials: A
authors.lastname: Lucas
authors.forename: M N
authors.initials: MN
authors.lastname: Martinez
authors.forename: S C
authors.initials: SC
authors.lastname: Sutton
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods / Q000662:veterinary; D018592:Cross-Over Studies; D012107:Research Design; D013678:Technology, Pharmaceutical / Q000379:methods*; D013810:Therapeutic Equivalency; D014481:United States; D014486:United States Food and Drug Administration / Q000592:standards; D019155:Veterinary Drugs / Q000493:pharmacokinetics*
chemical_list: D019155:Veterinary Drugs