DRUG PRODUCT PERFORMANCE IN VIVO

1. COPS DSU
DEPARTMENT OF PHARMACEUTICS
SUBMITTED TO :
Dr. JOSEPHINE LENO JENITHA
ASST. PROFESSOR
DEPARTMENT OF PHARMACEUTICS PRESENTED BY:
SAGAR.G
M. PHARM, 2nd SEM
DEPARTMENT OF PHARMACEUTICs
ADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
BIOAVAILABILITY AND BIOEQUIVALENCE
Purpose of bioavailability studies
Relative and absolute bioavailability

2. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
• Defined as “ the release of the drug substance from the drug product
leading to bioavailability of the drug substance”
• Bioavailability related to both pharmacodynamic response and adverse
effects
• Performance tests relate the quality of the drug product to efficacy and
safety
• Bioavailability studies ->Drug product performance ->changes in
physicochemical properties of the drug substance, formulation of the
drug, manufacturing process
• These studies are used in the development of new and generic drug
products
Drug Product Performance

3. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Bioavailability and Bioequivalence
Bioavailability Bioequivalence
• Links the in vivo
performance of the drug
product of a new drug
product to the original
formulation that was used
in clinical safety and
efficacy studies
• Drug product
performance tests that
compare the
bioavailability of the same
active pharmaceutical
ingredient from one drug
product to a second
product (reference)
BA and BE can be considered as measures of the drug product
performance in vivo

4. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Rate and Extent of absorption of unchanged drug from its dosage form is
known as bioavailability
Bioavailable Dose
The dose available to patient.
Systemic Availability
Amount of drug that reaches systemic circulation (i.e. extent of
bioavailability).
Bioavailable fraction(F)
The fraction of administered dose that enters systemic circulation.
Bioavailability
Definition
Bioavailable Dose
Administered Dose
F=

5. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
BA studies are carried out for...
Bioavailability studies performed for
both approved active drug ingredients
and not yet approved for marketing by
FDA
As standards like identity, strength,
quality and purity should be met
un-marketed drugs which do not
have full NDA approval by FDA, in
vitro / in vivo bioequivalence studies
must be performed
In vivo bioavailability studies are also
performed for new formulations of active
ingredients that have full NDA approval
These studies are useful in determining
safety and efficacy of drug products.

6. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Objectives of Bioavailability studies
Development of suitable dosage form for new drug entity
Development of new formulations of existing drugs
Determination of influence of excipients, patient related
factors and possible interactions with other drugs on
efficiency of absorption.
Control of quality of drug product during early stages of marketing.

7. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
During early drug development, BE 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
BE Studies in New Drug Development
• BE study designs are used to support new formulations of previously
approved products
• Examples:
-> New fixed-dose combination version of two products approved for
co-administration
-> Modified-release versions of immediate release products

8. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Post-approval, in vivo BE studies may be needed to support regulatory
approval of
Major changes in formulation
Manufacturing
Site in comparison to reference formulation (usually the prechange
formulation)

9. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Drug product performance and new drug product development for NDA
Active Pharmaceutical
Ingredient (drug substance)
Clinical drug
product
Marketed drug product (Brand)
Post approval changes
Clinical efficacy and safety studies
PK/BA studies
Dissolution profiles
and/or bioequivalence
studies
Dissolution profiles and/
or bioequivalence studies
Drug product performance can be determined by in vivo BE studies or in vitro by
comparative drug dissolution studies

10. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
• A multisource drug product is a drug product that contains the same
active drug substance in the same dosage form and is marketed by more
than one pharmaceutical manufacturer
• Single-source drug products are drug products for which the patent has
not yet expired or has certain exclusivities so that only one
manufacturer can make it
• Single-source drug products are usually brand-name (innovator) drug
products
• After the patent and other exclusivities for the brand-name drug
expires, a pharmaceutical firm may manufacture a generic drug product
that can be substituted for the branded drug product
BE Studies in Generic Drug Development (ANDA)

11. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
• The generic drug manufacturer must demonstrate that the generic
drug product is bioequivalent and therapeutically equivalent to the
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
• In vitro – drug dissolutions / release profiles

12. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Generic Drug Product Development
Generic drug
product
Active
Pharmaceutical
ingredient (drug
substance)
Comparative dissolution
profiles and/ or BE studies
to approved RLD
Dissolution profiles
plus bioequivalence
studies, if required
Post approval Changes

13. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Bioavailability and Bioequivalence Studies
• Bioavailability studies are used to define the effect of changes in the
physicochemical properties of the drug substance and the effect of the
drug product (dosage form) on the pharmacokinetics of the drug
• 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 bioequivalent and therapeutically equivalent
(as defined above), then the clinical efficacy and the safety profile of
these drug products are assumed to be similar and may be
substituted for each other

14. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Relative and Absolute Availability
• The systemic exposure of a drug in a
designated formulation (generally
referred to as treatment A or as reference
formulation) is compared
with that of
administered
formulation (generally referred to as
treatment B or test formulation)
in
the same drug a reference
• In relative bioavailability study, the AUCs
of the two formulations are compared as
follows:
• Absolute bioavailability compares the
bioavailability of the active drug in the
systemic circulation following
extravascular administration with the
bioavailability of the same drug following
intravenous administration
• IV administration is considered to be
100% absorbed
• For an oral formulation, the absolute
bioavailability is calculated ass follows:

15. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
• Frequently used in regulatory submissions
• For assessing how a new formulation impacts bioavailability
Types:
1. Assessment of new formulation - Oral formulation – oral solution as
reference
2. Food-effect - Studies to characterize food effects – oral bioavailability of
drug product given with meal (usually a high-fat, high-calorie meal) is
compared
-> The drug product given under fasting conditions is treated as the
reference treatment
3. Drug- drug interaction – to determine increase or decrease in
bioavailability in the presence of the interacting drug
Relative Bioavailability

16. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
• Used in developing new formulations of existing immediate-release drug
products
• Example – modified release versions or new fixed dose combination
formulations
• For modified release formulations – approved immediate release product is
the reference product
• For fixed dose products combinations, reference can be single entity drug
products administered either separately or concurrently according to an
approved combination regimen
• Used to compare the systemic bioavailability from a new pre market
formulation to an existing marketed formulation

17. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
Clinical studies, bioavailability studies and bioequivalence studies
BA studies
• Define the
effect of changes
in the
physicochemical
properties of the
drug substance
and
manufacturing
process
BE studies
• To compare
the
bioavailability
of the same
drug from
various drug
products
Clinical studies
• Safety and
efficacy of a
drug product

18. COPS DSU
DEPARTMENT OF PHARMACEUTICSADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS
• Applied Biopharmaceutics and Pharmacokinetics, Seventh edition
by Leon Shargel & Andrew B.C. Yu
• Wikipedia/Bioavailability.
• Shargel leon, WU Pong Susanna, B.C. YU Andrew, Applied
Biopharmaceutics and Pharmacokinetics, 7th edition, rights by
McGraw-hill
Reference

19. COPS DSU
DEPARTMENT OF PHARMACEUTICS
THANK YOU
ADVANCED BIOPHARMACEUTICS AND PHARMACOKINETICS