Drug Product performance M.pharm Syllabus

1. DRUG PRODUCT
PEFORMANCE IN-VIVO
Submitted by,
Feba Elsa Mathew
2nd semester M.Pharm
Submitted to,
Mrs. Juna Brigit Chacko
Asst. professor
Dept. of Pharmaceutics

2. CONTENTS
 Bioavailability and Bioequivalence: Drug product performance
 Purpose of bioavailability studies
 Relative and Absolute availability

3. 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.
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.

4. BIOAVAILABILITY
 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.
 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.

5. BIOEQUIVALENCE
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.

6. 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
(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)

7. Drug product performance and new drug product
development for NDAs.

8. Equivalent drug product performance is generally demonstrated by an in vivo bioequivalence study
in normal healthy volunteers.
Equivalent drug product performance may be demonstrated in vitro using comparative dissolution
profiles
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
postapproval changes. It is termed as SUPAC (scale-up and postapproval 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.

9. Bioequivalence Studies in Generic Drug Development
(ANDA)
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. 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.

10. 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.
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 drug product formulations.

11. 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 approval of new and generic drugs throughout the
world.
Clinical studies are used to determine the safety and efficacy of drug products.

12. 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.
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.

13. RELATIVE AND ABSOLUTE AVAILABILITY
A drug product’s bioavailability provides an estimate of the relative fraction of the
administered dose that is absorbed into the systemic circulation
Determining the fraction (f) of administered dose absorbed involves comparing the drug
product’s systemic exposure (represented by the concentration-versus-time or
pharmacokinetic profile) with that of a suitable reference product.
For systemically available drug products, bioavailability is most often assessed by
determining the area under the drug plasma concentration-versus-time profile (AUC).
The AUC is considered the most reliable measure of a drug’s bioavailability, as it is directly
proportional to the total amount of unchanged drug that reaches the systemic circulation.

14. Figure shows how the drug concentration-versus-time profile is used to identify the
pharmacokinetic parameters that form the basis of bioavailability and bioequivalence
comparisons.

15. Absolute Bioavailability
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.
Intravenous drug administration is considered 100% absorbed.
The route of extravascular administration can be inhaled, intramuscular, oral, rectal,
subcutaneous, sublingual, topical, transdermal, etc.
The absolute bioavailability is the dose-corrected AUC of the extravascularly
administered drug product divided by the AUC of the drug product given
intravenously.
Thus, for an oral formulation, the absolute bioavailability is calculated as follows:

16. Fabs is the fraction of the dose absorbed, expressed as a percentage
AUCpo is the AUC following oral administration
Div is the dose administered intravenously
AUCiv is the AUC following intravenous administration
Dpo is the dose administered orally
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).

17. Relative Bioavailability
In a relative bioavailability study, the systemic exposure of a drug in a designated
formulation (generally referred to as treatment A or reference formulation) is
compared with that of the same drug administered in a reference formulation
(generally referred to as treatment B or test formulation).
In a relative bioavailability study, the AUCs of the two formulations are compared as
follows:

18. Frel is the relative bioavailability of treatment (formulation) A, expressed as a
percentage
AUCA is the AUC following administration of treatment (formulation) A
DA is the dose of formulation A
AUCB is the AUC of formulation B; and
DB is the dose of formulation B

19. Relative bioavailability studies used in drug development include studies to characterize
food effects and drug–drug interactions.
In a food-effect bioavailability study, oral bioavailability of the drug product given with food
(usually a high-fat, high-calorie meal) is compared to oral bioavailability of the drug product
given under fasting conditions. The drug product given under fasting conditions is treated as
the reference treatment.
The goal of a drug–drug interaction study is to determine whether there is an increase or
decrease in bioavailability in the presence of the interacting drug. The general drug–drug
interaction study design compares drug relative bioavailability with and without (reference
treatment) the interacting drug.

20. Relative bioavailability studies are used in developing new formulations of existing immediate-
release drug products, such as new modified-release versions or new fixed-dose combination
formulations.
In the case of a new modified-release version, the reference product is the approved
immediate-release product.
In the case of a new fixed-dose combination, the reference product can be the single-entity
drug products administered either separately (ie, three treatments for a fixed-dose combination
doublet) or concurrently according to an approved combination regimen (ie, two treatments).
Relative bioavailability study designs are also commonly used for bridging formulations during
drug development, for example, to evaluate how drug systemic availability from a new
premarket formulation compares with that from an existing premarket formulation.

21. REFERENCE
Applied Biopharmaceutics & Pharmacokinetics Seventh Edition: Leon Shargel, Andrew
B.C. Yu, page no: 488-491