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CHAPTER OBJECTIVES

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  • Define bioavailability, bioequivalence, and drug product performance.

  • Explain why certain drugs and drug products have low 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.

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DRUG PRODUCT PERFORMANCE

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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. Thus, performance tests relate the quality of a drug product to clinical safety and efficacy. Bioavailability studies are drug product performance studies used to define the effect of changes in the physicochemical properties of the drug substance, the formulation of the drug, and the manufacture process of the drug product (dosage form). Drug product performance studies are used in the development of new and generic drug products.

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Bioavailability is one aspect of drug product quality that links the in vivo performance of a new drug product to the original formulation that was used in clinical safety and efficacy studies. 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 can be considered as measures of the drug product performance in vivo.

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Bioequivalence Studies in New Drug Development (NDA)

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During drug development, bioequivalence studies are used to compare (a) early and late clinical trial formulations; (b) formulations used in clinical trials and stability studies, if different; (c) clinical trial formulations and to-be-marketed drug products, if different; and (d) product strength equivalence, as appropriate. Bioequivalence study designs are used to support new formulations of previously approved products, such as a new fixed-dose combination version of two products approved for coadministration, or modified-release versions of immediate-release products. Postapproval, in vivo bioequivalence studies may be needed to support regulatory approval of major changes in formulation, manufacturing, or site, in comparison to reference formulation (usually the prechange formulation) (Fig. 16-1).

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FIGURE 16-1

Drug product performance and new drug product development for NDAs. Drug product performance may be determined in vivo by bioequivalence studies or in vitro by comparative drug dissolution studies. BA = bioavailability.

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