Introduction to Bioavailability and Bioequivalence

Definitions and Concepts

Bioavailability is defined by the United States Food and Drug Administration (FDA) as the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action.
- However, this official definition lacks precision.
- Consider the statement with respect to the site of drug action: while it is generally assumed that drug concentration in blood, plasma, or serum correlates with pharmacologic response, this is not applicable to all drugs.
- Furthermore, the actual bioavailability testing as outlined in regulations does not focus on determining drug concentration at the site of action but rather in systemic circulation.
- In rare cases where measuring blood levels is not feasible, bioavailability testing may be substituted with a pharmacologic or clinical test.
To refine the understanding of bioavailability, we can delineate it more precisely: Bioavailability encompasses both the relative amount of the therapeutic moiety (in the form of the parent drug, an active metabolite, or an active moiety of a prodrug) that enters systemic circulation and the rate at which the drug appears in it.
Contrary to common misconceptions, bioavailability is not directly indicative of clinical effectiveness.
Clinical effectiveness is influenced by a myriad of factors, including disease states and nutritional status, and the various elements that affect absorption (such as food intake, type and amount of food, circadian rhythms, age, etc.).
- Therefore, tests conducted on small sample sizes can only be interpreted as biological quality control evaluations under very specific conditions.
A drug product is defined as a finished dosage form; this includes tablets, capsules, solutions, suppositories, etc., containing the active drug ingredient, generally without necessary association with inactive ingredients.
- It should be noted that the term "active drug ingredient" implicitly includes prodrugs, despite not being explicitly stated.
Pharmaceutical Equivalents will refer to drug products containing identical amounts of the identical active drug ingredient—specifically, the same salt or ester of the same therapeutic moiety in identical dosage forms.
- They may not contain the same inactive ingredients but must meet identical standards of identity, strength, quality, and purity, including potency, content uniformity, disintegration times, and dissolution rates.
On the other hand, Pharmaceutical Alternatives consist of drug products that contain the same therapeutic moiety or its precursor but differ in the amount, dosage form, or salt or ester.
- Each drug product must individually adhere to its respective standard of identity, strength, quality, and purity.
While bioavailability measures the amount and rate of the drug or active moiety reaching systemic circulation (and is obligatory for any new drug or drug product), bioequivalence seeks to demonstrate that other drug products are biologically comparable to an already approved product in terms of performance.
Bioequivalence issues can arise when two or more pharmaceutical equivalents or alternatives—despite compliance with applicable in vitro standards—are administered at the same molar dose but yield inequivalent bioavailability.
- This scenario could indicate inadequacy in current in vitro standards or that products lack proper labeling to reflect their different pharmacokinetic behaviors.
- In public health terms, it is crucial that all products containing the same active ingredient be interchangeable, necessitating their bioequivalence or requiring distinct labeling to indicate a different pharmacokinetic profile for specific uses.
Bioequivalent drug products are characterized as pharmaceutical equivalents or alternatives whose rate and extent of absorption do not exhibit significant differences when given at the same molar dose of the therapeutic moiety under similar experimental conditions, whether in single or multiple dose studies.
- Some pharmaceuticals might be equivalent in absorption extent but differ in rates, yet still be classified as bioequivalent if such differences are intentional, adequately reflected in the labeling, and are medically insignificant for effective body drug concentrations in chronic use.
- To ensure bioequivalence, the FDA has established stringent requirements for both in vitro and/or in vivo testing of specified drug products, which must be fulfilled as a prerequisite for market approval.