Bioavailability and bioequivalence studies

Bioavailability methods , types of Bioavailability and bioequivalence studies

1. BIOAVAILABILITY AND BIOEQUIVALENCE
STUDIES
Prof R. Nagaraju
Institute of Pharmaceutical Technology
Sri Padmavathi Mahila Visvavidyalayam
( Women’s University) Tirupati

2. BIOAVAILABILITY:
Definedastherateandextenttowhichactive
ingredientsabsorbedfromadrugproduct
andbecomeavailableatsiteofaction.
Therateorrapidityatwhichdrugisabsorbed
isanimportantconsiderationintreatmentof
acuteconditionssuchasasthmaattackorin
pain.
Extentofabsorptionisofspecialsignificance
intreatmentofchronicconditionslike
hypertension,epilepsyetc.

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
Primarystagefordevelopmentofsuitabledosage
formfornewdrugentity.
Determinationofinfluenceofexcipients,patient
relatedfactorsandpossibleinteractionswithother
drugsonefficiencyofabsorption.
Developmentofnewformulationofexistingdrug
Controlofqualityofdrugproductduringearlystages
ofmarketinginordertodetermineinfluenceof
processingfactors,storageandstabilityondrug
absorption.

5. TYPES OF BIOAVAILABILITY
Absolute Bioavailability
Itissystemicavailabilityofdrugafterextra
vascularadministration(eg.oral,rectal,
transdermal)comparedtoIVdosing.
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.
F
r = (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

9. PLASMA DRUG CONCENTRATION:

10. Contd……
t
max
time required to reach maximum drug concentration
after drug administration.
t
maxused as an approximate indication of drug
absorption rate
C
max
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

12. TRAPEZOIDAL METHOD
AUC = (C
O + C
1)(t
1 –t
0)/2 + (C
1+C
2)(t
2-t
1)/2 + ------+ (C
n-1+C
n)(t
n-t
n-1)/2
+ C
p0/k

13. INTEGRATION METHOD
The rate of change of plasma concentration(C) is described as
dc/dt= rate of absorption –rate of elimination = K
a X
a–KX
Where, k
aand K absorption and elimination rate constant
X
aand 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/K
a)
Or simply AUC from t=0 to t=∞, equal to

14. URINARY DRUG EXCRETION DATA:

15. Contd….
Du
∞
:is Cumulative amount of drug excreted in urine
related directly to total amount of drug absorbed.

16. Contd….
dD
u/ 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:
Itisarelativetermthatcomparesdrugproductswithrespecttoa
specificcharacteristicsorfunctionortoadefinedsetofstandards.
TypesofEquivalencies
ChemicalEquivalence:
Twoormoredrugproductscontainthesamelabeledchemical
substanceasanactiveingredientinthesameamount.
PharmaceuticalEquivalence:
Twoormoredrugproductsareidenticalinstrength,quality,
dissolutioncharacteristics,theymayhoweverdifferin
containingdifferentexcipients.

20. Bioequivalence:
Thedrugsubstanceintwoormoreidenticaldosageforms,
reachesthesystemiccirculationatthesamerelativerateand
tothesamerelativeextenti.e.theirplasmaconcentration–
timeprofileswillbeidenticalwithoutsignificantstatistical
differences.
TherapeuticEquivalence:
Twoormoredrugproductsthatcontainthesame
therapeuticallyactiveingredient,elicitidentical
pharmacologiceffectsandcancontrolthedisease
tothesameextent.

21. BIOEQUIVALENCE
Pharmaceuticalequivalentswhoserateandextentof
absorptionarenotstatisticallydifferentwhen
administeredtopatientsorsubjectsatthesamemolar
doseundersimilarexperimentalconditions
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
(AUC
0→∞), T
maxand C
max
elimination rate constant K and elimination half life (t
1/2)
multiple dose studies
(AUC
0→t), t
max, C
min, C
maxand percent fluctuation
STASTICAL INTERPRETATION OF BIOEQUIVALENCE DATA
ANOVA is applied
Range of test formulation is 80-120%

27. REFERENCES:
1.Applied Biopharmaceuticsand Pharmacokinetics-5
th
edition by Leon Shargel, Susanna Wu-PONG, Andrew
B.C.YU. Page no; 453-498
2.Bioavailability and Bioequivalence in Pharmaceutical
Technology by TapanKumar Pal, M.Ganesan; Page
no: 9-29
3.Biopharmaceuticsand pharmacokinetics a treatise by
D.M.Brahmankar, Sunil B. Jaiswal; Page no: 282-305
4.Biopharmaceuticsand Pharmacokinetics by
G.R.Chatwal; Page no: 189-200
5.Textbook of Biopharmaceuticsand Pharmacokinetics
by SarfarazNiazi; Page no: 61-62