BIOAVAILABILITY AND BIOEQUIVALENCE

Chapter Objectives
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
DRUG PRODUCT PERFORMANCE
 Drug product performance, 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).
 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.
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.”
Relative bioavailability studies compare two drug product formulations.
A bioequivalence study is a specialized type of relative bioavailability study.
Bioequivalence is defined as “the absence of a significant difference in the rate
and extent to which the active ingredient or active moiety becomes available at
the site of drug action when administered at the same molar dose under similar
conditions in an appropriately designed study.”
Bioavailability and bioequivalence data play pivotal roles in regulatory
submissions for marketing
Bioequivalence studies are used to compare the bioavailability of the same
drug (same salt or ester) from various drug products.
If the drug products are pharmaceutically equivalent, bioequivalent, and
therapeutically equivalent (as defined by the regulatory agency such as the
FDA), then the clinical efficacy and the safety profile of these drug products
are assumed to be similar and may be substituted for each other.
Bioequivalence Studies in New Drug Development (NDA)
 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 co-administration, or modified-release versions of immediate-release
products.
 Post-approval, 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 pre-change formulation)
(Fig. 16-1).
 The initial safety and clinical efficacy studies during new drug development may use a
simple formulation such as a hard gelatin capsule containing only the active ingredient
diluted with lactose.
 If the new drug demonstrates appropriate human efficacy and safety, a to-be-marketed
drug product (eg, compressed tablet) may be developed.
 Since the initial safety and efficacy studies were performed using a different
formulation (ie, hard gelatin capsule), the pharmaceutical manufacturer must
demonstrate that the to be marketed drug product demonstrates equivalent drug product
performance to the original formulation (Fig. 16-1).
 After the drug product is approved by the FDA and marketed, the manufacturer may
perform changes to the formulation. These changes to the marketed drug product are
known as post-approval changes.
 These post-approval changes, often termed SUPAC (scale-up and post-approval change)
based on several FDA guidance documents), could include a change in the supplier of
the active ingredient, a change in the formulation, a change in the manufacturing
process, and/or a change in the manufacturing site.
 In each case, the manufacturer must demonstrate that drug product performance did not
change and is the same for the drug product manufactured before and after the SUPAC
change. As shown in Fig. 16-1.

Bioequivalence Studies in Generic Drug Development (ANDA)

 Comparative drug product performance studies are important in the development of
generic drug products (Fig. 16-2).
 A generic drug product is a multisource drug product that has been approved by the
FDA as a therapeutic equivalent to the reference listed drug product (RLD) (usually the
brand or innovator drug product) and has proven equivalent drug product performance.
 Clinical safety and efficacy studies are not generally performed on generic drug
products.
 Since the formulation and method of manufacture of a drug product can affect the
bioavailability and stability of the drug, the generic drug manufacturer must
demonstrate that the generic drug product is pharmaceutically equivalent, bioequivalent,
and therapeutically equivalent to the comparator brand-name drug product.
 Drug product performance comparison for oral generic drug products is usually
measured by in vivo bioequivalence studies in normal healthy adult subjects under
fasted and fed conditions.
 Similar to the brand-name drug product manufacturer, the generic drug manufacturer
may make changes after FDA approval in the formulation, in the source of the active
pharmaceutical ingredient, manufacturing process, or other changes.
 For any post-approval change, the manufacturer must demonstrate that the change did
not alter the performance of the drug product.
REFERENCE & KEYS

Applied Biopharmaceutics & pharmacokinetics by LEON

SHARGEL Sixth Edition, Chapter# 16, Page # 403-443.