1.
BIOAVAILABILITY,
BIOEQUIVALENCE AND
BCS CLASSIFICATION
Guided By
Pallavi. K M.Pharm,
Department of Pharmaceutics.
Presented By
10AB1R0042,
Shajeeya Amren. Sk,
IV B. Pharm,
Vignan Pharmacy College.
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2.
Bioavailability
Objectives of bioavailability
Factors effecting bioavailability
Measurement of bioavailability
Bioequivalence
Terms to know in Bioequivalence
Types of Bioequivalence studies
BCS classification
Conclusion
Acknowledgement
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Regulatory Definition
(21 CFR 320.1(a)):
“Bioavailability means 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.”
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5.
Primary stages of development of a suitable dosage form for
new drug entity.
Determination of influence of excipients, patient related factors
and interaction with other drugs on the efficiency of absorption.
To evaluate the absolute systemic availability of active drug
substance from a dosage form.
Control quality of drug in early stages of development.
Develop new formulation for existing drug.
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Systemic availability the amount that reaches
systemic circulation is simply known as availability.
Absolute bioavailability of a drug product may be
comparing the respective bioavailabilites after an
oral and iv bolus injection.
Relative bioavailability is defined as a ratios of
bioavilabilities of a drug product and reference
standard.
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Absolute bioavailability
Relative bioavailability
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Three
major
factors
that
effecting
bioavailability:1. Pharmaceutical factors
2. Patient related factors
3. Routes of administration.
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Bioavailability
Pharmaceutical
Factors
Physicochemical
Factors
Patient Related
Factors
Route Of
Administration
Pharmaco Technical
Factors
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The methods available are:Pharmacokinetic (Indirect) Method
Pharmacodynamic (Direct) Method.
Selection of method depends upon :Nature Of The Study
Nature Of Dosage Form
Analytical Method Development.
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11.
T max
Plasma
data
AUC
Indirect
methods
dx u/dt
Urinary
data
Bio
availability
Direct
methods
C max
Acute
pharmacolog
ical response
Clinical
response
Xu
Tu
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Plasma Drug Concentration Vs Time Graph
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Cmax
- Maximum plasma concentration .
The concentration of drug at therapeutic response is elicited.
Increase with increase in dose and with an increase in absorption.
Tmax
- Time to reach maximum concentration
Indicates rate of absorption.
It decrease as the rate of absorption increases.
AUC - Area under the curve.
Indicates the extent of drug absorption from a dosage form.
The fraction of dose that reaches the systemic circulation.
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Rate of urinary excretion of drug versus time plot
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Maximum urinary excretion rate
It is obtained from peak of plot between rate of urinary
excretion data versus time.
Time for maximum excretion rate
It is the maximum time required to reach maximum excretion
rate.
Cumulative amount of drug excreted
It is the drug excreted in urine till the drug level falls zero.
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Sl. no
Plasma data
Urinary data
1.
Maximum plasma
concentration
C max
Time to maximum
concentration
T max
Area under the curve
AUC
Maximum urinary excretion
rate
2.
3.
Time to maximum
excretion rate
Cumulative amount of drug
excreted
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Acute pharmacological response
When bioavailability measurement by pharmacokinetic method is
difficult, an acute pharmacologic effect are taken into consideration
Dose
response
curve
Can
be
determined
by
construction
of
Pharmacological effect Vs Time curve
E.g.: pupil diameter, heart rate or BP can be useful as an index of drug
bioavailability
Clinical response / Therapeutic response
Best method Clinical response of the drug for which it is intended to be
used is measured
Based on clinical response to the drug formulation given to the patients
E.g.: for anti-inflammatory drugs, reduction in inflammation is determined
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Bioequivalence
When the drug from two or more similar dosage form
reaches the general circulation at the same relative rate
and extent then the dosage forms are termed as
Bioequivalent.
Statistical significant differences are observed in the
bioavailability
of
Bio-inequivalence.
two
or
more
drug
products,
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When significant changes are made in the manufacture of the
marketed formulation
When a new generic formulation is tested against the
innovator's marketed product
Comparison of availability of drug substance from different
dosage forms
when changes in formulation have occurred after an
innovator product has been approved.
Comparison of availability's of same dosage form produced
by different manufactures
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Equivalence
Chemical equivalence
Clinical equivalence
Pharmaceutical Equivalence
Bioequivalence
Therapeutic equivalence
Comparable Dosage Form
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Bioequivalence
studies
In vivo
Oral immediate
release
In vitro
Non oral
immediate
release
Modified
release with
systemic action
Clinical studies
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The
word
BCS
refers
Biopharmaceutics
Classification System for Drugs, which is based
Aqueous solubility and Permeation of drug through
GI tract.
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Valuable tool for formulation scientist for selection of
design of formulated drug substance.
Efficiency of drug development and review process.
To Reduces cost and time of approving Scale- up and post
approval challenges.
Applicable
in
both
pre-clinical
and
clinical
drug
development process.
Works as a guiding tool in development of various oral drug
delivery systems.
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It’s a theoretical basis for correlating in vitro drug dissolution
with in vivo availability, developed by Dr. Gordon Amidon et
al(1995) and submitted at FIP, Brazil.
Based on Aqueous solubility and intestinal permeability.
Classification on Fick’s first law
J w = Pw C w
Where J w = Drug flux across the GUT wall
Pw = Permeability of membrane
C w = Drug concentration at GI membrane
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Sl.
No
Class
Solubility
Permeabili
ty
Examples
Comment
1.
I
High
High
Metoprolol
Dilitiazem
Verapamil
propranolol
Well absorbed, their
absorption rate is
higher than excretion
rate. IVIVC observed
2.
II
Low
High
Glibenclamide
Phenytoin
Danazol
Limited by dissolution
rate, IVIVC occurs
with high dose of
drugs.
3.
III
High
Low
Cimetidine
Acyclovir
Neomycin B
captropil
Absorption is limited
by the permeation rate
but the drug solvates
fast. No IVIVC
4.
IV
Low
Low
Chlorothiazide
Taxol
fuoemide
Neither soluble nor
absorbed in mucosa.
No IVIVC.
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Sl. no
Class of drug
solubility
permeability
1
Ia
High and site
independent
High and site
independent
2
Ib
High and site
independent
Depend on site and
narrow therapeutic
window
3
II a
Low and site
independent
High and site
independent
4
II b
Low and site
independent
Depend on site and
narrow therapeutic
window
5
V a : acidic
Variable
variable
6
V b : basic
Variable
variable
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Berstrom
et
al
(2003) modified BCS to six classes
Development is based on calculated surface area, solubility
and permeability.
Based on solubility and permeability was classified into 6
classes as low, intermediate and high.
Based on surface area Non-polar part - good solubility, Polar
part – good permeability.
Three compounds are wrongly classified amitryptiline,
acyclovir and doxycycline
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Applications in both pre - clinical and clinical drug
development.
Regulatory toll for replacement of certain be studies.
Reduces the time in the drug development process as
time is an important aspect in industry.
Leads to direct and indirect savings of pharmaceutical
companies.
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Solubility profile should be determined
PH range of 1-7.5 at 37
1 c.
The drug is said to be highly soluble in a solution with
defined pH when the highest dose is soluble in 250ml of
aqueous media over pH range of 1-7.5.
Shake flask method is used to for invitro determination of
solubility.
E.g. Acid or base titration methods.
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Sl. No
Terms
Parts Of Solute Required To
Dissolve One Part Of Solvent
1.
2.
3.
Very Soluble
Freely Soluble
Soluble
Less Than 1 Part
1 To 10 Part
10 To 30 Part
4.
5.
6.
Sparingly Soluble
Slightly Soluble
Very Slightly Soluble
Practically Insoluble Or
Insoluble
30 To 100 Part
100 To 1000 Part
1000 To 10,000 Part
7.
More Than 10,000 Part
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Highly permeable is said to be when the
extent of absorption is determined 90% or more than it
Human studies include mass balance studies, absolute
bioavailability, intestinal perfusion methods in vivo studies
Drug absorption
Prediction in humans is by In vitro
permeability by intestinal tissue and mono layer of epithelial
cells
E.g. Caco – 2cells or TC – 7
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There are some methods to determine permeability of drug in
GI track include
1. In vivo intestinal perfusion studies in humans
2. In vivo intestinal perfusion studies in animals
3. In vitro permeation in experiments using excised human or
animal tissue intestinal tissue
4. In vitro permeation experiments across monolayer of
cultured human intestinal cells.
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Dissolution class includes IR product following
conditions to be applied
Dissolving not less than 85% amount of drug with in
30 min
Using USP Dissolution apparatus 1 at 100 rpm in a
volume of 900ml or less
In 0.1 N HCl or simulated gastric fluid or PH 4.5
buffer and PH 6.8 buffer or stimulated intestinal fluid.
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(FDA Guidelines for industry , 2000; Adomin et al, 1995)
Applicable in NDA’s, ANDA’s and post approval changes.
Primary evidence of safety and efficacy.
Significant in pre and post approval changes in
pharmaceutical equivalents.
BCS eliminates the need human subjects to reference and
test products.
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Conclusions
Every drug in the development process must undergo BABE
studies.
Primary stages of drug development and formulation of
dosage includes Bioavailability.
Presently, there is international harmonization of regulatory
requirements for bioequivalence studies
BCS eliminates unnecessary drugs exposures to healthy
subjects and provides economic relief and maintain high
public standard for therapeutic equivalence.
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Previous GPAT Bits Covered In
This Topic
A drug (200 mg dose) administered in tablet form and as intravenous
injection (50 mg dose) showed AUC of 100 and 200 microgram hr/mL,
respectively. The absolute availability of the drug through oral
administration is : (GPAT 2012)
(A) 125% (B) 250 % (C) 12.5% (D) 1.25%
Half life is the time it takes for the concentration of drug to halve, no matter
what the starting concentration is. If the drug is eliminated by First order
kinetics how many half-lives it takes for a drug for total elimination of 97%
of drug (GPAT 2010)
a)
3 half-lives B) 5 half-lives
C) 8 half-lives
D) 10 half-lives
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Previous GPAT Bits Cover In This
Topic (cont….)
The characteristic of non-linear pharmacokinetics include ( GPAT 2011)
(A) Area under the curve is proportional to the dose
(B) Elimination half-life remains constant,
(C) Area under the curve is not proportional to the dose
(D) Amount of drug excreted through remains constant
The percentage of a dose of drug product administered via extravascular
route that is systemically available as compared to an intravenous dose is
referred as (GPAT 2010)
A) Absolute bioavailability
C) AUC
B) Relative bioavailability
D) T max
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Previous GPAT Bits Cover In This
Topic (cont….)
Which conditions does not apply as per Indian lw while conducting
single dose bioavailability study of an immediate release product?
(GPAT 2011)
a)
Sampling Period should be at least three t ½ el
b) Sampling should represent pre-exposure, peak exposure and post
exposure phases.
c) There should be at least four sampling points during elimination
phase
d) Sampling should be continued till measured AUC is at least equal
to 80% of AUC
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List Of References
Guidelines for bioavailability and bioequivalence studies,
CDSCO, directorate general of health service, Ministry of family and health
welfare, new Delhi.
Applied Biopharmaceutics and pharmacokinetics, 6th edition, pg no 431-433 –
leon shargel
Remington the scientists practice of pharmacy 21st edition, vol 1 1037-1046
Biopharmaceutics and clinical pharmacokinetics 4th edition, pg no 3, 352,171 –
robert notori
Biopharmaceutics and pharmacokinetics a treatise pg no- 315-363, - DM
Bramankar
Biopharmaceutics and clinical pharmacokinetics – pg 7-9, 146-175, milo gibadi
Martins physical pharmacy and pharmaceutical sciences 6th edition pg no -232
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List Of References (cont…..)
Biopharmaceutics and pharmacokinetics pg no 331-356, - v. venkateshvarulu
Biopharmaceutics classification a strategic tool for classifying drug substances
ISSN 2230-8407 – rohila seema www.irjponline.com
What is bioavailability and bioequivalence Candida agency for drug and technology
for health www.cadth.generics/ca
Bioavailability and Bioequivalence- Jake J. Thiessen, Ph.D, University of Toront,
Canada, Email jj.thiessen@utoronto.ca
Bioavailability and Bioequivalence Studies, “ Standard Approach”, www.ivivc.com
Bioavailability & bioequivalence trials, Shubha Rani, Ph.D, Synchron Research
Services Pvt. Ltd., Ahmadabad, drshubha@synchronresearch.com
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Acknowledgement
I sincerely thank and regards
to my guide K. Pallavi, and
other staff members for their
support. I would also thank
my
family,
friends
and
finally our beloved Principal
Dr. P. Srinivasa Babu.
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