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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

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Bioavail

ability

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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.”

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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.

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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

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Assessment Of Bioequivalence

Bioequivalence studies

In vivo

Oral immediate release

Non oral immediate

release

Modified release with

systemic action

In vitro

Clinical studies

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Biopharmace

utics Classification

System

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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

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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

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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

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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.

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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.

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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

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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

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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

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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.

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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

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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 B) Relative bioavailability

C) AUC 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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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

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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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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

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Any queries ?

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For ur attention