Bio availiility equivalence

8/2/2019 Bio availiility equivalence

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BA-BE


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Contents

Bioavailability

Factors affecting bioavailability

Methods of assessing bioavailability

Bioequivalence

When BE studies are necessary

When BE studies are not necessary

BE measure


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Bioavailability

It describes the rate and extent to which theactive drug ingredient is absorbed from a drugproduct and becomes available at the site of

drug action.

Since pharmacologic response is generally relatedto the concentration of drug at the receptor site,the availability of a drug from a dosage form is a

critical element of a drug product's therapeutic


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In most cases one is concerned with the extent ofabsorption of drug, (that is, the frac-tion of the dosethat actually reaches the bloodstream) since thisrepresents the "effective dose" of a drug.

This is generally less than the amount of drug actuallyadministered in the dosage form. In come cases,notably those where acute conditions are being treated,one is also concerned with the rate of absorption of adrug, since rapid onset of pharmacologic action is

desired.

How-ever, drug concentrations usually cannot bereadily measured directly at the site of action.

Therefore, most bioavailability studies involve the

determination of drug concentration in the blood orurine.


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Types of bioavailability

Absolute

bioavailability

Relative

bioavailability


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Absolute bioavailability

F, is the fraction of an administered dose which actuallyreaches the systemic circulation, and ranges from F = 0(no drug absorption) to F = 1 (complete drugabsorption).

It is established in comparison to IV formulation.

Since the total amount of drug reaching the systemiccirculation is directly proportional to the area under theplasma drug concentration vs time curve (AUC), F isdetermined by comparing the respective AUCs of thetest product and the same dose of drug administeredintra-venously.

The IV route is the reference standard since the dose is,


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F=AUCev

AUCiv

where AUCEV and AUCIV are,respectively, the area under theplasma concentra-tiontime curve

following the extravascular andintravenous administration of a givendose of drug. Knowledge of F is

needed to determine an appropriate


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Relative /Comparativebioavailability

refers to the availability of a drugproduct as compared to anotherdosage form or manufactured by

another manufacturer.

These measurements determine the

effects of formulation differ-ences ondrug absorption.

The relative bioavailability of product


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Example: Data for Absolute and RelativeBioavailability

The bioavailability for Product B and Product C is 50%(F = 0.5) and 40% (F = 0.4), respectively.

Drug product AUC(mcg/ml) X hr

A IV injection 100

B oral dosage formreference standard

50

C oral dosage form generic product

40


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Factors affectingbioavailability


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Before the therapeutic effect of anorally administered drug can berealized, the drug must be absorbed.

The systemic absorption of an orallyadministered drug in a solid dosageform is comprised of three distinct

steps:

disintegration of the drug product


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Factors

Pharmaceuticalfactors /

Dosage form relatedfactors

Pharmacologicalfactors/

Patient relatedfactors


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Pharmaceutical factors /

Dosage form related factors

Physicochemical properties ofdrug

Formulations andmanufacturing variables

Particle size Amount of disintegrant

Crystalline structure Amount of lubricant

Degree of hydration of salt Nature of diluent

Salt form Compression force


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Pharmacological factors/

Patient related factors

Physiologic factors Interactions with othersubstances

Gastric emptying Food

Intestinal motility Other drugs

Diseased state Fluid volume

First pass effect

Age

Gender


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Pharmaceutical factors /Dosage form related factors

Particle size A drug usually dissolves more rapidly when its surface

area is increased by decreasing particle size.

For this reason, poorly soluble, slowly dissolving drugsare often marketed in microfined or finely particledform to increase their absorption.

For certain drugs like penicillin G and Erythromycin,micronization is avoided as they are unstable in gastricfluids. Reduction of particle size with consequent

increase in their dissolution rate result in moreextensive de radation of dru and so BA will decrease.


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Crystalline structure

amorphous forms have fasterdissolution rate and betterbioavailability compared to theircrystalline forms.


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Degree of hydration of salt

Many drugs take up the water toproduce crystalline forms called thehydrates.

Anhydrous forms have fasterdissolution rate and better

bioavailability than hydrous forms


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Salt form

Dissolution rate of a particular salt is usually

different from that of the parent compound.

Salt form have better dissolution profile andfast bioavailability.

e.g. sodium tolbutamide and sodiumsecobarbital have better BA than tolbutamideand secobarbital.


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Nature of excipients

Lactose and polysorbate 80 are wetting agentsenhances solvent penetration in drug particles ensures faster dissolution and quicker absorption.

magnesium stearate, a lubricant, is waterinsoluble and

waterrepellent. It retards drug dissolution bypreventing contact between drug and aqueous GIfluids. Thus, increasing amount of magnesium stearateresults in a slower dissolution rate of the drug, anddecreased bioavailability.


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The nature of the dosage form itself may have aneffect on drug absorption characteristics.

The decreasing bioavailability is related to thenumber of steps involved in the absorption process

after administration.

The greater the number of steps, the slower is theavailability and the greater is the potential for

bioavailability differences to occur.


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Pharmaceutical factors ofbioavailability

Oral administration of drug

1

2

Tablet/capsule

Powders/suspensions

Solutions

Disintegration

Dissolution

Available for absorption throughGIT

To fine particles

Drug in solution


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Fastest availability

Slowest availability

Solutions

Suspensions

Capsules

Tablets

Coated tablets

Controlled releaseformulations


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Pharmacological factors/Patient related factors

Gastric emptying Factors that accelerate gastric emptying, permit drugs

to reach the e large absorptive surface area of small

intestine sooner, and increase the BA.

The converse is also true and important.

Prompt gastric emptying is also important for drugsthat are unstable in acidic gastric fluid e.g. Penicillin

Factors affecting gastric emptying rate


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Intestinal motility

Since the proximal small intestine is the optimumsite for drug absorption, a change in the stomachemptying rate is likely to alter the rate, andpossibly the extent, of drug absorption.

e.g. Propantheline increases and Metoclopramidedecreases BA of Digoxin in increasing or reducingtransit time respectively through small intestine.


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Diseased state

Since drugs are administered to patients, it isimportant to consider the effects of the disease on

the bioavailability of the drug.

Gastrointestinal

diseases

Otherdiseases


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Gastrointestinal diseases

achlorhydria

gastric acid secretion is decreased so increase inpH. This increases absorption of weakly acidic drugslike Aspirin, because at higher pH, its dissolution isfaster.

Crohns disease(chronic inflammation of ileum)

disproportionate absorption of individual

components from tablets of cotrimoxazoleabsorption of trimethoprim is decreased and that ofsulfamethoxazole is increased.

Gastroenteritis


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Other diseases

some diseases concerning thecardiovascular sys-tem and the liver mayalso alter circulating drug levels after oraldosing.


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First pass effect

Decreased bioavailability and diminishedtherapeutic response of drugs havingsignificant first pass effect.

e.g.

Ldopa

Morphine


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Age

Affects bioavailability due to differences in drugmetabolism.

Drug metbolizing enzymes are deficient in the

newborn, making them more susceptible to manydrugs. This deficit is made up in first few months.

Metabolism capability is also decreased in thea ed.


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Interaction with food

Gastrointestinal absorption is favored by an emptystomach while absorption rate is reduced afteringestion of food. But still the nature of drugfoodinteractions is complex and unpredictable.

However rate and extent of absorption of certainantibiotics is reduced after meals.

Absorption of tetracycline is reduced if taken with milkor milk products (forms poorly absorbed complex withcalcium ions)

Vitamin C keeps iron in its ferrous form and therefore

increases its bioavailability


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Food may interact with drugs, either:

Directly

Chemically i.e. chelation

Physically i.e. by adsorbing the drug or acting as abarrier to absorption.

Indirectly - through physiological changes in GI tractlike:

gastric emptying is delayed


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Effect of Food on Drug Absorption

Reducedabsorption

Delayedabsorption

Increasedabsorption

Ampicillin Diclofenac Diazepam

Aspirin Digoxin Metoprolol

Penicillins Furosemide Riboflavin

Tetracycline Sulfadiazine GriseofulvinEthanol Acetaminophen Hydralazine


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Drug Drug interactions

Antacids containing Al, Ca and Mg and haematinicscontaining iron causes reduced bioavilability of

Tetracycline. Because the resultant chelated complex ispoorly absorbed.

Barbiturates reduce BA of several drugs due toenzymatic induction.

Probenecid blocks Penicillin excretion and thusenhances its BA.


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Fluid volume

The volume of fluid with which an orally administereddose is taken can also affect a drug's bioavailability.

Drug administration with a larger fluid volume will

generally improve its dissolution characteristics andmay also result in more rapid stomach emptying.

Thus, more efficient and more reliable drug absorption

can be expected when an oral dosage form isadministered with a lar er volume of fluid.


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Methods of assessingbioavailability


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Demonstration of aclinically significant effect

such clinical studies are complex,expensive, time consuming and

require a sensitive and quantitativemea-sure of the desired response.

Also response is often quite variable,requiring a large test population.

This method is used in initial stages


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Quantification of

pharmacologic effect This method is based on the

assumption that a given intensity of

response is associated with aparticular drug concentration at thesite of action

However, monitoring ofpharmacologic data is often difficult,

precision and reproducibility are


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Urinary excretion data

measures the cumulative amount of unchanged drugexcreted in the urine. These studies involve collection ofurine samples and the determination of the total quantity ofdrug excreted in the urine as a function of time.

These studies are based on the premise that urinaryexcretion of the unchanged drug is directly proportional tothe plasma concentration of total drug. Thus, the totalquantity of drug excreted in the urine is a reflection of the

quantity of drug absorbed from the gastrointestinal tract.

This technique of studying bioavailability is most useful forthose drugs that are not extensively metabolized prior tourinary elimination.


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As a ruleofthumb, determination of bioavailabilityusing urinary excretion data should be conductedonly if at least 20% of a dose is excretedunchanged in the urine after an IV dose.

In practice, these estimates are subject to a highdegree of variability, and are less reliable thanthose obtained from plasma concentrationtimeprofiles. Thus, urinary excretion of drug is notrecommended as a substitute for bloodconcentration data; rather, these studies should beused in conjunction with blood level data for

confirmatory purposes.


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Blood level studies

most common type of studies based on assumption that there is a

direct relationship between theconcentration of drug in blood orplasma and the concentration of

drug at the site of action.

Following the administration of a

single dose of a medication, blood


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1. AUCThe area under the plasma

concentrationtime curve

The AUC is proportional to the totalamount of drug reaching thesystemic circulation. It is used toquantitate the extent of drugabsorption.


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i.e.

Cmax is proportional to the rate ofabsorption and Tmax is inversely propor-

tional to the absorption rate.

faster the absorption of a drug,higher the Cmax will be and the less

time it will take to reach the


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The absence of a significantdifference in the rate and extent towhich the drug(active ingredient) inpharmaceutical equivalents orpharmaceutical alternatives become

available at the site of action whenadministered at same molar doseunder similar conditions.


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Pharmaceutical equivalents

drug products that contain identical amounts

of identical active ingredients i.e. same salt orester of the same therapeutic moiety, inidentical dosage forms, but not necessarilycontaining the same inactive ingredients.

e.g.

Diclofenac sodium Diclofenac sodium

Tablet Tablet

50mg 50mg


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Pharmaceutical alternatives

drug products that contain identicaltherapeutic moiety but not necessarilyin the same amount or dosage form or

as the same salt or ester.

e.g.Diclofenac sodium Diclofenacsodium

Tablet Capsule


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Bio availiility equivalence