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A outline description of Bioavailabilty, Bioequivalence and BCS Clasisification
Citation preview
1
Guided By
Pallavi. K M.Pharm,Department of Pharmaceutics.
Presented By
10AB1R0042,Shajeeya Amren. Sk,
IV B. Pharm,Vignan Pharmacy College.
BIOAVAILABILITY, BIOEQUIVALENCE AND BCS CLASSIFICATION
Bioavailability
Objectives of bioavailability
Factors effecting bioavailability
Measurement of bioavailability
Bioequivalence
Terms to know in Bioequivalence
Types of Bioequivalence studies
BCS classification
Conclusion
Acknowledgement
3
Bioavail
ability
4
BioavailabilityRegulatory 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.”
5
Objectives Of BioavailabilityPrimary 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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Terms To Be Understand 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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Formulae Of Bioavailability
Absolute bioavailability
Relative bioavailability
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Factors effecting Bioavailability
Three major factors that effecting
bioavailability:-
1. Pharmaceutical factors
2. Patient related factors
3. Routes of administration.
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Factors effecting bioavailability
Bioavailability
Pharmaceutical Factors
Physicochemical Factors
Pharmaco -Technical Factors
Patient Related Factors
Route Of Administration
Methods For Assessment Of Bioavailability
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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Assessment Of Bioavailability
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Bioavailability
Indirect methods
Plasma data
T max
C max
AUC
Urinary data
dx u/dt
X u
T u
Direct methods
Acute pharmacological response
Clinical response
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Indirect Methods - Plasma Data
Plasma Drug Concentration Vs Time Graph
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Plasma DataCmax - 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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Indirect Method – Urinary Data Analysis
Rate of urinary excretion of drug versus time plot
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Urinary Data
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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Correlation Between Plasma And Urinary Data
Sl. no Plasma data Urinary data
1. Maximum plasma concentrationC max
Maximum urinary excretion rate
2. Time to maximum concentrationT max
Time to maximum excretion rate
3. Area under the curveAUC
Cumulative amount of drug excreted
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Correlation Between Plasma And Urinary Data (Cont…)
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Direct MethodsAcute 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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Bioequi
valence
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BioequivalenceBioequivalence
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 two or more drug products,
Bio-inequivalence.
21
Objectives Of BioequivalenceWhen 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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Terms To Be Understood In Bioequivalence
Equivalence
Chemical equivalence
Clinical equivalence
Pharmaceutical Equivalence
Bioequivalence
Therapeutic equivalence
Comparable Dosage Form
23
Assessment Of Bioequivalence
Bioequivalence studies
In vivo
Oral immediate release
Non oral immediate
release
Modified release with
systemic action
In vitro
Clinical studies
24
Biopharmace
utics Classification
System
25
BCS Classification 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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Objectives Of BCS Classification
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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Principle Of BCS ClassificationIt’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
Where J w = Drug flux across the GUT wall
Pw = Permeability of membrane
C w = Drug concentration at GI membrane
J w = Pw C w
28
BCS For Conventional Dosage FormSl. No
Class Solubility Permeability
Examples Comment
1. I High High MetoprololDilitiazemVerapamilpropranolol
Well absorbed, their absorption rate is higher than excretion rate. IVIVC observed
2. II Low High GlibenclamidePhenytoinDanazol
Limited by dissolution rate, IVIVC occurs with high dose of drugs.
3. III High Low CimetidineAcyclovirNeomycin Bcaptropil
Absorption is limited by the permeation rate but the drug solvates fast. No IVIVC
4. IV Low Low ChlorothiazideTaxolfuoemide
Neither soluble nor absorbed in mucosa. No IVIVC.
BCS CLASSIFICATION SYSTEM FOR EXTENDED RELEASE DRUG PRODUCTS
Sl. no Class of drug solubility permeability
1 I a High and site independent
High and site independent
2 I b 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
29
30
Extension To BCS 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
31
Benefits Of Knowing BCS Category Of A Compound
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.
32
Solubility Determination
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.
33
Terms Of Approximate SolubilitySl. No Terms Parts Of Solute Required To
Dissolve One Part Of Solvent1. Very Soluble Less Than 1 Part2. Freely Soluble 1 To 10 Part3. Soluble 10 To 30 Part4. Sparingly Soluble 30 To 100 Part5. Slightly Soluble 100 To 1000 Part6. Very Slightly Soluble 1000 To 10,000 Part7. Practically Insoluble Or
InsolubleMore Than 10,000 Part
34
Permeability
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
35
Determination of permeability
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.
DISSOLUTION
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.36
37
Regulatory Applications Of BCS
(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.
38
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.
Conclusions
39
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
40
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 B) Relative bioavailability
C) AUC D) T max
41
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
42
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
List Of References
43
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 [email protected]
Bioavailability and Bioequivalence Studies, “ Standard Approach”, www.ivivc.com
Bioavailability & bioequivalence trials, Shubha Rani, Ph.D, Synchron Research
Services Pvt. Ltd., Ahmadabad, [email protected]
44
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.
Acknowledgement
45
Any queries ?
46
For ur attention