2. BIOAVAILABILITY:
Defined as the rate and extent to which active
ingredients absorbed from a drug product
and become available at site of action.
The rate or rapidity at which drug is absorbed
is an important consideration in treatment of
acute conditions such as asthma attack or in
pain.
Extent of absorption is of special significance
in treatment of chronic conditions like
hypertension, epilepsy etc.
3. FACTORS AFFECTING BIOAVAILABILITY OF
DRUGS FROM ITS DOSAGE FORM
1. Drug Substance Physicochemical Properties
2. Pharmaceutical Ingredients
3. Dosage form Characteristics
4. Physiological Factors And Patient
Characteristics
5. Route Of Administration
4. OBJECTIVE/ PURPOSE OF BIOAVAILABILITY
STUDIES
Primary stage for development of suitable dosage
form for new drug entity.
Determination of influence of excipients, patient
related factors and possible interactions with other
drugs on efficiency of absorption.
Development of new formulation of existing drug
Control of quality of drug product during early stages
of marketing in order to determine influence of
processing factors, storage and stability on drug
absorption.
5. TYPES OF BIOAVAILABILITY
Absolute Bioavailability
It is systemic availability of drug after extra
vascular administration (eg.oral, rectal,
transdermal) compared to IV dosing.
F = (AUC)PO/(Dose)PO
(AUC)IV / (Dose)IV
For drug given intravascularly (IV), F = 1
For all extra vascular route of administration,
such as oral route, F>1
6. RELATIVE BIOAVAILABILITY:
Also called as comparative bioavailability.
Defined as availability of drug from drug product
as compared to reference standard.
Fr = (AUC)A/(Dose)A
(AUC)B/ (AUC)B
Where drug product B is reference standard
7. HUMAN VOLUNTEERS – HEALTHY SUBJECTS
VERSUS PATIENTS
Ideally BA studies should be carried out in
patients
Bioavailability studies usually performed in
Young healthy male adult volunteers
Age 20-40 years
Body weight + 10%
Under restricted dietary and fixed activity condition
Medical examination should also be performed
8. METHODS FOR ASSESSING BIOAVAILABILITY
PHARMACOKINETIC METHOD
Plasma drug concentration:
Time for peak plasma concentration (tmax)
Peak plasma drug concentration (Cmax)
Area under plasma drug concentration time curve (AUC)
Urinary drug excretion
Cumulative amount of drug excreted in urine (Du)
Rate of drug excretion in urine (dDu/dt)
Time for maximum urinary excretion (t)
PHARMACODYNAMIC METHOD
Acute pharmacological response
Therapeutic response
IN VITRO STUDIES
Drug dissolution
10. Contd……
tmax
time required to reach maximum drug concentration
after drug administration.
tmax used as an approximate indication of drug
absorption rate
Cmax
represents maximum plasma drug concentration
obtained after oral administration.
Provide therapeutic response
also provide warning of toxic level of drug
AUC:
measurement of extent of drug bioavailability
11. MEASUREMENT OF AUC
PHYSICAL METHOD
Cut and weigh method
Using planimeter
TRAPEZOIDAL METHOD
INTEGRATION METHOD
13. INTEGRATION METHOD
The rate of change of plasma concentration(C) is described as
dc/dt = rate of absorption – rate of elimination = Ka Xa – KX
Where, ka and K absorption and elimination rate constant
Xa and X are amount of drug in GIT and body respectively
On integration,gives
C = A (e-Kt – e-Kat)
And the total area under curve (AUC), for which total integral time zero and
Infinity is given by
AUC = A (1/K – 1/Ka)
Or simply AUC from t=0 to t=∞, equal to
15. Contd….
Du∞ : is Cumulative amount of drug excreted in urine
related directly to total amount of drug absorbed.
16. Contd….
dDu / dt:
t∞ : Total time for drug to be excreted.
17. PHARMACODYNAMIC METHODS:
1. Acute pharmacological response:
Change in ECG or EEG reading, pupil
diameter, BP is related to time course of given
drug.
Disadvantage
more variable method
accurate correlation is difficult
2. Therapeutic response:
18. THERE ARE SOME DEFINITIONS FROM
2003 ORANGE BOOK:-
Pharmaceutical alternative
Pharmaceutical equivalent
Pharmaceutical substitution
Therapeutic alternative
Therapeutic substitution
19. 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.
Types of Equivalencies
Chemical Equivalence:
Two or more drug products contain the same labeled chemical
substance as an active ingredient in the same amount.
Pharmaceutical Equivalence:
Two or more drug products are identical in strength, quality,
dissolution characteristics, they may however differ in
containing different excipients.
20. Bioequivalence:
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 i.e. their plasma concentration –
time profiles will be identical without significant statistical
differences.
Therapeutic Equivalence:
Two or more drug products that contain the same
therapeutically active ingredient, elicit identical
pharmacologic effects and can control the disease
to the same extent.
21. BIOEQUIVALENCE
Pharmaceutical equivalents whose rate and extent of
absorption are not statistically different when
administered to patients or subjects at the same molar
dose under similar experimental conditions
Basic design of BE studies determined by
scientific questions to be answered
nature of reference material
Availability of analytical method
Ethical consideration with regard to testing in human
22. ELEMENTS OF BA STUDY PROTOCOL
1. Title
2. Study objective
3. Study design Title
a. Drug product
Test product
Reference product
b. Dosage regimen
C. Sample collection
schedule
d. Fasting/meal schedule
e. Analytical method
4. Study population
a. Subjective
b. Subject selection
Medical history
Physical examination
5. Clinical procedures
a. Dosage and drug
administration
b. Biological sampling
schedule
c. Activity of subject
6. Ethical consideration
a. Basic principle
b. Informed consent
c. Indication for subject
withdrawal
d. Adverse reaction and
emergency procedure
7. Facilities
8. Data analysis
9. Drug accountability
10. Appendix
23. STUDY DESIGN
INCLUDE
Fasting study
required for all immediate release and modified
release dosage form
both male and female are used in study
Food intervention study
generally conducted using meal condition
the test meal is high fat and high calorie meal
Multiple dose study
comparing equal dose of test and reference product
performed in adult, healthy subjects
24. CROSS OVER DESIGN
LATIN SQUARE CROSS OVER DESIGN:
each formulation is administered just once to each
subject and once in each study period
Subject
1
2
3
4
5
6
Study period 1
A
B
C
A
C
B
Study period 2
B
C
A
C
B
A
Study period 3
C
A
B
B
A
C
25. REPLICATED CROSS OVER DESIGN:
same reference and same test are given twice to
same subject
reference to reference and test to test
comparison may also be made
Sequence 1
Sequence 2
Period 1
T
R
Period 2
R
T
Period 3
T
R
Period 4
R
T
26. EVALUATION OF DATA:
ANALYTICAL METHOD
must be validated for accuracy, precision, sensitivity and specificity
use of more than one analytical method during BE studies may not
be valid
PHARMACOKINETIC EVALUTION OF DATA
single dose studies
(AUC0→∞), Tmax and Cmax
elimination rate constant K and elimination half life (t1/2)
multiple dose studies
(AUC0→t), tmax , Cmin, Cmax and percent fluctuation
STASTICAL INTERPRETATION OF BIOEQUIVALENCE DATA
ANOVA is applied
Range of test formulation is 80-120%
27. REFERENCES:
1. Applied Biopharmaceutics and Pharmacokinetics-5th
edition by Leon Shargel, Susanna Wu-PONG, Andrew
B.C.YU. Page no; 453-498
2. Bioavailability and Bioequivalence in Pharmaceutical
Technology by Tapan Kumar Pal, M.Ganesan; Page
no: 9-29
3. Biopharmaceutics and pharmacokinetics a treatise by
D.M.Brahmankar, Sunil B. Jaiswal; Page no: 282-305
4. Biopharmaceutics and Pharmacokinetics by
G.R.Chatwal; Page no: 189-200
5. Textbook of Biopharmaceutics and Pharmacokinetics
by Sarfaraz Niazi; Page no: 61-62