3 of 22

Objectives of bioavailability

Primary stage of development of suitable dosage form for a new drug entity to obtain evidence of its therapeutic utility.

Determination of influence of excipients patient related factors and possible interaction with other drugs on the efficiency of absorption.

Development of new formulations of the existing drugs.

Control of quality of a drug product during the early stage of marketing in order to determine the influencing of processing factors , storage and stability on drug absorption.

Comparision of availability of a drug substance from different dosage form or from same dosage form produced by different manufacturers.

4 of 22

Considerations in IN-VIVO bioavailability study design

Abosolute bioavailability : when systemic availability of a drug administered orally is determined in comparision to its intravenous administration it is called as absolute bioavailability.

5 of 22

It is denoted by symbol F.

It is used to characterise the drug inherent absorption properties from the e.v site .

i.v dose is selected as a standard because the drug is administered directly in to the systamic circulation (100% bioavailability) and avoids absorption step.

i.m dose can also consider as std if the drug is poorly water soluble .

6 of 22

Oral can also be consider as std but having some draw backs.
1 . Limits the pharmacokinetic treatment to one compartment model only. & not applicable to 2 compartment kinetics & all ph.kinetic parameters cannot be assed.

2. Differentiation b/w the fraction of dose unabsorbed and that metabolized is difficult.

3. If the rate of oral absorption is not sufficiently greater than the rate of elimination , the true elimination rate constant cannot be computed.

7 of 22

Relative or comparitive bioavailability.

When the systamic availability of a drug after oral administration is compared to that of an oral standard of the same drug ( such an aqueous, or nonaqueous solution or suspension ) it is referred as relative or comparitive bioavailability.

8 of 22

The better alternative is thus multiple dose study which offers several advantages.
1) more accurately reflects the manner in which the drug will be used clinically.
2) Allows blood level to be measured at the same conc encountered therapeutically.
3) Easy to predict the peak and valley characteristics of drug since the bioavailability is determined at steady state.
4) Requires collection of fewer blood samples.
5) Drug blood levels are higher due to cumulative effect which makes its determination possible even by the less sensitive analytical method.
6) Can be ethically performed by patients because of the therapeutic benefit to the patient.

9 of 22

Single dose vs Multiple dose studies:
The dose to administered for a bioavailability study is determined from the preliminary clinical experiments.

Single dose bioavailability studies are very common.

They are easy , offer less exposure to drugs and are less tedious.

It is difficult to predict the steady state characteristics of a drug and intersubjects variability with such studies.

More over sufficiently long sampling period are necessary in order to get reliable estimates of terminal half life which is needed for correct calculation of total AUC .

10 of 22

7) small intersubject variability is observed in such a study which allows use of fewer subjects.

8) better evaluation of performance of a controlled released formulations is possible.

9) Nonlinearity in pharmacokinetics ,if presented can easily detected.

10) Eliminates the need for a long washout period between doses. More over the switch over from one formulation to the other is possible at steady state.

11 of 22

Limitations of multiple dose studies

1) Tedious requires more time to complete
2) More difficult and costly to conduct (require prolong monitering of subjects).

3) Poor compliance by subjects.

4) Greater exposure of subjects to the test drug increasing the potential for adverse reactions.

In multiple dose study one must ensure that the steady state has been reached . For this the drug should be administered for 5 to 6 eliminations half lives before collecting the blood samples.

12 of 22

Human volunteers –healthy subjects vs patients

Patients will be benifited from the study.

Reflects the better therapeutic efficacy of a drug.

Drug absorption pattern in disease state can be evaluated.

Avoids the ethical quandry of administering drugs to healthy subjects.

13 of 22

Bioequivalence: It is relative term which denotes that the drug substance in two or more identical dosage forms reaches the systemic circulation at the same relative rate and to the same relative extent ie. Their plasma conc profile will be identical with out significant statistical differences . When statistically significant difference are observed in the bioavailability of two or more drug products bio-inequivalence is indicated.
Goals of BE
Establish that a new formulation has therapeutic equivalence in the rate and extent of absorption to the reference drug product.
Important for linking the commercial drug product to clinical trial material at time of NDA
Important for post-approval changes in the marketed drug formulation

14 of 22

Need /Objective for Bioequivalence

A new product is intended with be substituted for an approved medicinal product as a pharmaceutical equivalent or alternative , the equivalent with this product should be shown or justified.

To ensure clinical performance of such drug products bioequivalence studies should be performed.

Bioequivalence studies are conducted if there is

A risk of bio-inequivalence

A risk of pharmacotherapeutic failure (or) diminished clinical safety

15 of 22

Equivalence : It is a relative term that compares drug products with respect to a specific characteristics or function or to a defined set of standards .

Chemical equivalence it indicates that two or more drug products contain the same labelled chemical substance as an active ingredient in the same amount.

Pharmaceutical Equivalence: this term implies that two or more drug products are identical in strength, quality, purity, content uniformity and disintegration and dissolution characteristics. they may , how ever differ in containing different excipients.

16 of 22

Therapeutic equivalence: This term indicates the two or more drug products that contains the same therapeutically active ingredients elicit identical pharmacological effect and can control the disease to the same extent.
TYPES OF BIOEQUIVALENCE STUDIES:
In-vivo
In-vitro

INVIVO BIOEQUIVALENCE STUDIES

The following sequence of criteria is useful assending the need for in-vivo studies

Oral immediate release product with systemic action

* indicated for serious conditions requiring assured response.

* Narrow therapeutic margin

* Pharmacokinetics complicated by absorption ˂70% or absorption window , nonlinear kinetics presystemic elimination ˃ 70%

17 of 22

* Un favourable physicochemical properties ie.

low solubility , metastable modification instability etc.

* Documented evidence for bioavailability problems.

* No relavent data available , unless justification by applicant that in-vivo study is not necessary.

2. Non oral immediate release product.

3 . Modified release with systemic action.

18 of 22

IN-VITRO BIOEQUIVALENCE STUDIES:

1. The drug product differ only in strength of the active substance it contains provided all conditions held-
* Pharmacokinetics are linear.
* Qualitative composition is the same .
* The ratio b/w the active substance and the excipients is same .
* Both products are produced by the same manufacturer at the same production site.

* A bioavailability or bioequivalence study has been performed with the original product.

* Under the same test conditions the in-vitro dissolution rate is same.

19 of 22

2. The drug product has been slightly reformulated or the manufacturing method has been slightly modified by the original manufacturer in way that can convincingly argued to be ir- relavent for the bioavailability.

3. The product meet all of the following requirements
* The product is in the form of solution or solubilised (elixer, syrup ,tincture etc.)

* The product contains active ingredients in the same conc as the approved drug product.

* The product contains no excipients known to significantly effect absorption of the active ingredient.

20 of 22

4. An acceptable IVIVC and the in-vitro dissolution rate of new product is equivalent with that of the already approved medicinal product. More over

* The product is intended for topical administration (creams, ointments , gels) for local effect.

* The is product is for oral administration but not intended to be absorbed ( antacid, or radio opaque material.

* The product is administered by inhalation as a gas or vapour.

21 of 22

Elements of Bioequivalence study protocol

1) Title
a. Principal investigator
b. Project number and data

2) Study objective

3) Study design
a. Design
b. Drug products
i.Test product
ii. Reference product
C. Dosage regimen
d. Sample collection schedule
e. Housing
f. Fasting/ meals schedule
g. Analytical method

4) Study population
a. Subjects
b. Subject selection
i. Medicinal chemistry
ii. Physical examination
iii. Laboratory test
C. Inclusion/Exclusion criteria
i. Inclusion criteria
ii. Exclusion criteria
d. Restrictions/ Prohibitions

22 of 22

5. Clinical procedures
a. Dosage and drug administration
b. Biological sampling schedules
c. Activity of subjects
6. Ethical considerations
a. Basic principles
b. Institutional review board
c. Informed consent
d. Indication for subject withdrawl
e. Adverse reactions and emergency procedures
7. Facilities
8. Data analysis
a. Analytical validation procedure
b. Statistical treatment of data
9. Drug accountability
10. Appendix