Biopharmaceutics

Drug Product Performance, In Vivo

Bioavailability and Bioequivalence
 Drug Product Performance
• Drug product performance, in vivo, may be defined as
the release of the drug substance from the drug
product leading to bioavailability of the drug substance.

• Performance studies are used in the development of

new and generic drug products

• Bioavailability and bioequivalence can be considered as

measures of the drug product performance in vivo
 Bioavailability
• 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
 Absolute Bioavailability
• Absolute bioavailability of a drug is the systemic
availability of the drug after extravascular
administration of the drug and is measured by
comparing the area under the drug concentration–time
curve after extravascular administration to that after IV
administration
• Extravascular administration of the drug comprises
routes such as oral, rectal, subcutaneous, transdermal,
nasal, etc.
• Intravenous drug administration is considered 100%
absorbed

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 IV bolus
100

80
Concentration

Area under concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
6 Time
 Oral dosage form (product A)

100

80
Area under concentration
Concentration

60 curve (AUC)

40

20

0
0 5 10 15 20 25 30
7 Time
 Absolute Bioavailability

100 For the same dose

(IV vs. Oral), the
80
bioavailability is given
Concentration

by:
60

AUCoral
40 F
AUC IV
20

0
0 5 10 15 20 25 30
8 Time
 What about the dose?
• The absolute bioavailability is the dose-corrected AUC
of the extravascularly administered drug product
divided by the AUC of the drug product given
intravenously.
 What about the dose?
• Absolute availability, Fabs, may be expressed as a
fraction or as a percent by multiplying Fabs × 100.

• A drug given by the intravenous route will have an

absolute bioavailability of 100% (F= 1).

• A drug given by an extravascular route may have an

Fabs = 0 (no systemic absorption) and Fabs = 1.0
(100% systemic absorption).
• 0<Fabs<1
 Relative Bioavailability
• The relative bioavailability is the systemic
availability of a drug from one drug formulation
(A) compared to another formulation of the
same drug (B).

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 Relative Bioavailability

Oral Dosage form (Product A) Oral Dosage Form (Product B)

100 100

Area under
Area under concentration 80
80 concentration curve
curve (AUC)

Concentration
Concentration

60
(AUC)
60

40
40

20
20

0
0 5 10 15 20 25 30
0
0 5 10 15 20 25 30 Time
Time

For the same dose (Oral vs. Oral), the bioavailability is given by:
100

80
Concentration

60
AUCoral( A)
40
F
20 AUCoral( B)
12
0
0 5 10 15 20 25 30
Time
Dose Normalization
 Practice Problem
• The bioavailability of a new investigational drug was
studied in 12 volunteers. Each volunteer received either
a single oral tablet containing 200 mg of the drug, 5 mL
of a pure aqueous solution containing 200 mg of the
drug, or a single IV bolus injection containing 50mg of
the drug. The average AUC values are given in the table
below. From these data, calculate
– the relative bioavailability of the drug from the tablet
compared to the oral solution
– the absolute bioavailability of the drug from the tablet.

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 Practice Problem
Drug Product Dose (mg) AUC (ug. hr/mL)
Oral tablet 200 89.5
Oral solution 200 86.1
IV bolus injection 50 37.8

Relative bioavailability 89.5/86.1= 1.04 or 104%

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 Comments about the case
• Because F, the fraction of dose absorbed from the
tablet, is less than 1, the drug from the oral tablet is
not completely absorbed systemically, as a result of
either poor oral absorption of the drug itself,
formulation effects that reduce oral bioavailability, or
metabolism by first-pass effect (presystemic
elimination).

• The relative bioavailability of the drug from the

tablet is approximately 100% when compared to the
oral solution.
 Comments about the case
• Results from bioequivalence studies may show that
the relative bioavailability of the test oral product is
greater than, equal to, or less than 100% compared
to the reference oral drug product.

• However, the results from these bioequivalence

studies should not be misinterpreted to imply that
the absolute bioavailability of the drug from the oral
drug products is also 100% unless the oral
formulation was compared to an intravenous
injection (completely bioavailable) of the drug.
 Bioequivalence
• 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 statistical

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.
 Bioequivalence Studies in New Drug Development
• During drug development, bioequivalence studies are used
to compare:
 early and late clinical trial formulations
 formulations used in clinical trials and stability studies, if
different.
 clinical trial formulations and to-be-marketed drug
products, if different.
 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.
 Bioequivalence Studies in New Drug Development
• 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
 Bioequivalence Studies in New Drug Development
• Equivalent drug product performance is generally
demonstrated by an in vivo bioequivalence study in
normal healthy volunteers.

• Under certain conditions, equivalent drug product

performance may be demonstrated in vitro using
comparative dissolution profiles
 Bioequivalence Studies in Generic Drug Development
• 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 (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.
 In Summary
• In summary, clinical studies are used to determine the safety and
efficacy of drug products.

• 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 manufacture process of the drug product (dosage form).

• Bioequivalence studies are used to compare the bioavailability

of the same drug (same salt or ester) from various drug
products.
 In Summary

• Bioavailability and bioequivalence can be considered as

performance measures of the drug product in vivo.

• 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.