Bioequivalence defined

Bioavailability, Bioequivalence, and Pharmacokinetics. Bioavailabihty can be defined as the amount and rate of absorption of a dmg into the body from an adrninistered dmg product. It is affected by the excipient ingredients in the product, the manufacturing technologies employed, and physical and chemical properties of the dmg itself, eg, particle size and polymorphic form. Two dmg products of the same type, eg, compressed tablets, that contain the same amount of the same dmg are pharmaceutical equivalents, but may have different degrees of bioavailabihty. These are chemical equivalents but are not necessarily bioequivalents. For two pharmaceutically equivalent dmg products to be bioequivalent, they must achieve the same plasma concentration in the same amount of time, ie, have equivalent bioavadabihties. 

When pharmaceuticals are administered to feed animals there is a special concern about the possible accumulation of drug residues in the animals tissues. Thus, in these bioequivalency studies it may be appropriate to carefully monitor parameters that define possible tissue accumulation [45]. 

The Chinchilli metric (24,27), defined as the ratio of the test region area over the reference region area, uses a reference region area specified by i L = 0.8i and Ru = 1.2R as upper/lower acceptance (bioequivalence) limits for the reference. This is compared with the test region area mentioned earlier. The procedure as such appears rather complicated. 

BioavaUabUity and bioequivalence are related terms but they can be confused. Bioavailabihty as defined earlier is also known as absolute bioavailability and is simply the fraction of the administered dose that reaches the systemic circulation it is therefore defined only in terms of the extent of drug absorption. However, in the Committee for Proprietory Medicinal Products (CPMP) guideline for the investigation of bioavailability and bioequivalence, the former is defined as the rate and extent to which the active substance of therapeutic moiety is absorbed from a pharmaceutical form and becomes available at the site of action. The reason that bioavailability has been defined in this way is because rate, as well as extent, is important when comparing the bioavailability of two pharmaceutical forms of an active substance to determine whether they are bioequivalent. Bioequivalence and comparative bioavaUabUity are discussed later but absolute bioavailabihty will be described first. 

Category 2 applications are defined as those that include clinical, preclinical or bioequivalence data for which there are two evaluation... 

During the 1990 Washington Conference on Analytical Methods Validation Bioavailability, Bioequivalence and Pharmacokinetic Studies [1], parameters that should be used for method validation were defined. The final report of this conference is considered the most comprehensive document on the validation of bioanalytical methods. Many multinational pharmaceutical companies and contract research organizations contributed to its final draft. This scientific meeting was sponsored by the American Association of Pharmaceutical Scientists (AAPS), the Association of Official Analytical Chemists (AOAC), and the U.S. Food and Drug Administration (FDA). The conference report has been used as a reference by bioanalytical laboratories and regulatory agencies worldwide. 

To document the bioequivalence of the drug product for which the manulacture has been changed, as defined in this guidance, compared to the drug product manufactured prior to the change or compared to the reference listed drug (RLD). 

As the bioequivalence rules are clearly defined, the study population must ensure a high level of standardization, making it sometimes difficult to extrapolate to patient settings. Typical enrolment criteria are ... 

An underlying premise of bioequivalence assessments is a clearly defined phar-macokinetic/pharmacodynamic relationship however, the relation between blood levels and effect is less clearly established for proteins [20]. 

For bioequivalence, dissolution profiles of two tablets are often compared. In this case, the difference factor and similarity factor are considered, defined by the equations... 

Aqueous solubility of ionizable molecules at different pH values is an important characteristic because it indicates the potential substance behavior in the stomach and intestinal tract and its potential impact on bioavailability. Moreover, it also provides important information for formulation scientists to define the class of a drug substance in the Biopharmaceutics Classification System (BCS), a regulatory guidance for bioequivalence studies. The BCS is a scientific framework proposed by the FDA to classify drug substances based on their aqueous solubility and intestinal permeability and defines important parameters in the selection of drug candidates into development. According to the BCS, drug substances are classified as shown in Table 12-4. 

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