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CHAPTER OBJECTIVES

  • Define bioavailability, bioequivalence, and drug product performance.

  • Explain why certain drugs and drug products have low bioavailability.

  • Distinguish between relative bioavailability and absolute bioavailability.

  • Explain why first-pass effect as well as chemical instability of a drug can result in low relative bioavailability.

  • Distinguish between bioavailability and bioequivalence.

  • Explain why relative bioavailability may have values greater than 100%.

  • Explain why bioequivalence may be considered as a measure of drug product performance.

  • Describe various methods for measuring bioavailability and the advantages and disadvantages of each.

  • Describe the statistical criteria for bioequivalence and 90% confidence intervals.

  • Explain the conditions under which a generic drug product manufacturer may request a waiver (biowaiver) for performing an in vivo bioequivalence study.

  • Define therapeutic equivalence and explain why bioequivalence is only one component of the regulatory requirements for therapeutic equivalence.

DRUG PRODUCT PERFORMANCE

Drug product performance,1 in vivo, may be defined as the release of the drug substance from the drug product leading to bioavailability of the drug substance. The assessment of drug product performance is important since bioavailability is related both to the pharmacodynamic response and to adverse events. Bioavailability studies are in vivo drug product performance studies that relate the physicochemical properties of the drug substance, the formulation of the drug and the manufacture process, to the expected clinical efficacy and safety of the drug product. Drug product performance studies are used in the development of both new and generic drug products.

Bioavailability studies are important to establish the in vivo performance of a new drug product. Bioequivalence studies are used to compare the performance of the original formulation that was used in clinical safety and efficacy studies to a to-be marketed drug product.2 Bioequivalence studies are drug product performance tests that compare the bioavailability of the same active pharmaceutical ingredient from one drug product (test) to a second drug product (reference). Bioavailability and bioequivalence are measures of the drug product performance in vivo.

1A glossary of terms appears at the end of this chapter.

2During new drug development, different dosage forms of the active drug may be formulated. The term “relative bioavailability” rather than “bioequivalence” may be used to compare the bioavailability of different dosage forms of the same drug.

PURPOSE OF BIOAVAILABILITY AND BIOEQUIVALENCE STUDIES

Bioavailability and bioequivalence studies are important in the process of approving pharmaceutical products for marketing. 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 (US-FDA, CDER, 2014a). Bioavailability data provide an estimate of the fraction of drug absorbed from the formulation and provide information about the pharmacokinetics of the drug. Relative bioavailability studies compare two or more drug product formulations. A bioequivalence study ...

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