Definitions

Absorption of the active moiety is a stipulation for systemically acting drugs that are administered by an extravascular route [1]. Bioavailability is defined as the rate and extent of absorption of the intact drug or active moiety. Studies that concern the evaluation of dose-linearity, potential food-drug interactions, and the pharmacokinetics after repeated administration are discussed in subsequent sections of this chapter. Alternative approaches, i.e., pharmacodynamic studies, to those described in this chapter might be necessary for locally acting drugs, where systemic exposure is not intended and cannot be assessed. However, if the bioavailability (or bioequivalence) of a drug can be determined by a pharmacokinetic study, a pharmacodynamic approach is not recommended.

Bioavailability and especially bioequivalence studies are generally performed throughout a product's life cycle, both before and after the drug approval. Bioequivalence studies are the principal basis for approval of abbreviated NDAs for generic drugs. These studies are essential for both efficacy and safety, by demonstrating that the pharmaceutical formulation gives reproducible drug exposure, and intended plasma levels of the active moiety. Bioequivalence studies are discussed in detail in the Biopharmaceutics section, and will not be discussed in this chapter.

The European Agency for the Evaluation of Medicinal Products (EMEA) has issued a new guidance document regarding investigations of bioavailability and bioequivalence in July 2001 [17]. In the United States, the requirements for bioavailability and bioequivalence studies for product approval are described by the Code of Federal Regulations (21 CFR 320), and more details are found in Chapter 2. In 21 CFR 320.1, bioavailability is defined as "the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. For drug products that are not intended -to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action."

As an additional support for adequate designs of bioavailability (and bioequivalence) studies, FDA has published several guidance documents regarding the general principles for these studies:

"Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations" (Revision 1, March 2003)

"Food-Effect Bioavailability and Fed Bioequivalence Studies" (December 2002)

"Statistical Approaches to Establishing Bioequivalence" (January 2001)

"Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations" (September 1997)

"Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System" (August 2000)

The guidance documents relating to bioequivalence and conditions where waivers are granted in lieu of in vivo studies are discussed in detail in the chapters in the Biopharmaceutics section of this book. It should be noted that the guidance documents are recommendations, and reflects the current thinking of the FDA. Alternative approaches than those recommended in the guidance documents may be employed if the requirements of the statutes in 21 CFR 320 are fulfilled.

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