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The research of bioavailability (BA) and/or bioequivalence (BE) plays an important role in the development of new drugs and their generic equivalents. The relative BA in terms of the rate and extent of drug absorption is considered predictive of clinical outcomes. When two formulations of the same drug or two drug products are claimed bioequivalent, it is assumed that they will provide the same therapeutic effect or that they are therapeutically equivalent.
BA refers to the degree and rate at which the active ingredient or active moiety of the drug is absorbed and available at the site of action. For most oral drug products, BA can be described by a whole-body exposure profile obtained by measuring concentrations of active ingredients and/or active moieties in blood or plasma over a while after administration. From a pharmacokinetic point of view, BA studies can also provide useful information on drug metabolism, transport, distribution and elimination, dose ratios, and the effect of nutrients on drug absorption. From a drug product performance view, BA studies also benchmark the performance of drug products used in clinical trials that provide evidence of safety and efficacy.
BE assesses the relative BA of two drug products, and thus, focuses on comparative drug product performance. BE documentation may be useful during the IND-NDA (New Drug Application) period to establish links between (i) early and late clinical trial formulations; (ii) formulations used in clinical studies and stability studies, if different; and (iii) clinical trial formulations and the to-be-marketed drug product.
Fig.1 Brief representation of workflow of BA/BE study. (Lohar, 2012)
BE limits or margins could be determined based on absolute change, relative change. The specified limit could be in turn based on an absolute change or relative change.
BE is concluded if the average BA of the test formulation is within ±20% of that of the reference formulation with a certain assurance. This decision rule is based on the additive model and not on relative or percent change. Thus, it is not employed commonly for most drug products.
BE is concluded if the average BA of the test formulation is within (80%, 125%) that of the reference formulation, with a certain assurance. Current FDA regulation adopts the 80/125 rule after log-transformation. That is, two drug products are said to be ABE if the 90% confidence interval of the ratio of geometric means of the primary PK responses (after log-transformation) is within the BE limits of 80% and 125%.
The assessment of BE of different drug products is based on the fundamental assumption that two products are equivalent when the rate and extent of absorption of the test/generic drug do not show a significant difference from the rate and extent of absorption of the reference/brand drug under similar experimental conditions as defined. As per the different regulatory authorities, BE studies are generally classified as:
The general descending order of preference of these studies includes pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.
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