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 the active drug ingredient is absorbed from a drug product and becomes available at the site of drug action.
Since pharmacologic response is generally related to 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 3/10/12

In most cases one is concerned with the extent of absorption of drug, (that is, the fraction of the dose that actually reaches the bloodstream) since this represents the "effective dose" of a drug. This is generally less than the amount of drug actually administered 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 a drug, since rapid onset of pharmacologic action is desired. However, drug concentrations usually cannot be readily measured directly at the site of action. Therefore, most bioavailability studies involve the determination of drug concentration in the blood or 3/10/12 urine.

Types of bio-availability

Absolute bioavailab ility

Relative bioavailab ility

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Absolute bioavailability

F, is the fraction of an administered dose which actually reaches the systemic circulation, and ranges from F = 0 (no drug absorption) to F = 1 (complete drug absorption). It is established in comparison to IV formulation. Since the total amount of drug reaching the systemic circulation is directly proportional to the area under the plasma drug concentration vs time curve (AUC), F is determined by comparing the respective AUCs of the test product and the same dose of drug administered intravenously.
3/10/12IV The

route is the reference standard since the dose is,

F = AUCev AUCiv

where AUCEV and AUCIV are, respectively, the area under the plasma concentration-time curve following the extravascular and intravenous administration of a given dose of drug. Knowledge of F is needed to determine an appropriate 3/10/12

Relative /Comparative bioavailability

refers to the availability of a drug product as compared to another dosage form or manufactured by another manufacturer. These measurements determine the effects of formulation differences on drug absorption. The relative bioavailability of product

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Data Bioavailability
Example:

for

Absolute
100 50 40

and

Relative

Drug product A IV injection B oral dosage formreference standard C oral dosage form generic product

AUC(mcg/ml) X hr

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

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Before the therapeutic effect of an orally administered drug can be realized, the drug must be absorbed. The systemic absorption of an orally administered drug in a solid dosage form is comprised of three distinct steps: disintegration of the drug product

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Factors
Pharmaceutical factors / Dosage form related factors Pharmacological factors/ Patient related factors

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Pharmaceutical factors / Dosage form related factors

Physicochemical properties of drug Particle size Crystalline structure Degree of hydration of salt Salt form 3/10/12 Formulations and manufacturing variables Amount of disintegrant Amount of lubricant Nature of diluent Compression force

Pharmacological factors/ Patient related factors

Physiologic factors Gastric emptying Intestinal motility Diseased state First pass effect Age Gender 3/10/12 Interactions with other substances Food Other drugs Fluid volume

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 drugs are often marketed in microfined or finely particled form to increase their absorption. For certain drugs like penicillin G and Erythromycin, micronization is avoided as they are unstable in gastric fluids. Reduction of particle size with consequent increase in their dissolution rate result in more 3/10/12 extensive degradation of drug and so BA will decrease.

Crystalline structure amorphous forms have faster dissolution rate and better bioavailability compared to their crystalline forms.

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Degree of hydration of salt

Many drugs take up the water to produce crystalline forms called the hydrates. Anhydrous forms have faster dissolution rate and better bioavailability than hydrous forms 3/10/12

Salt form

Dissolution rate of a particular salt is usually different from that of the parent compound. Salt form have better dissolution profile and fast bioavailability. e.g. sodium tolbutamide and sodium secobarbital have better BA than tolbutamide and 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 water-insoluble and water-repellent. It retards drug dissolution by preventing contact between drug and aqueous GI fluids. Thus, increasing amount of magnesium stearate results in a slower dissolution rate of the drug, and decreased bioavailability.
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The nature of the dosage form itself may have an effect on drug absorption characteristics. The decreasing bioavailability is related to the number of steps involved in the absorption process after administration. The greater the number of steps, the slower is the availability and the greater is the potential for bioavailability differences to occur.
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Pharmaceutical factors of bioavailability

Oral administration of drug
Tablet/capsule

1
To fine particles

Disintegration

Powders/suspensions

Dissolution

2
Drug in solution Solutions Available for absorption through GIT

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Fastest availability

Solutions Suspensions Capsules Tablets Coated tablets

Slowest availability

Controlled release formulations

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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 drugs that are unstable in acidic gastric fluid e.g. Penicillin

3/10/12 Factors affecting gastric emptying rate

Intestinal motility

Since the proximal small intestine is the optimum site for drug absorption, a change in the stomach emptying rate is likely to alter the rate, and possibly the extent, of drug absorption. e.g. Propantheline increases and Metoclopramide decreases BA of Digoxin in increasing or reducing transit time respectively through small intestine.
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Diseased state
Since drugs are administered to patients, it is important to consider the effects of the disease on the bioavailability of the drug.

Gastrointesti nal diseases

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Other diseases

Gastrointestinal diseases achlorhydria gastric acid secretion is decreased so increase in pH. This increases absorption of weakly acidic drugs like Aspirin, because at higher pH, its dissolution is faster. Crohns disease(chronic inflammation of ileum) disproportionate absorption of individual components from tablets of co-trimoxazoleabsorption of trimethoprim is decreased and that of sulfamethoxazole is increased.
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Gastroenteritis

Other diseases
some diseases concerning the cardiovascular system and the liver may also alter circulating drug levels after oral dosing.

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First pass effect

Decreased bioavailability and diminished therapeutic response of drugs having significant first pass effect.

e.g.

L-dopa
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Morphine

Age

Affects bioavailability due to differences in drug metabolism. Drug metbolizing enzymes are deficient in the newborn, making them more susceptible to many drugs. This deficit is made up in first few months. Metabolism capability is also decreased in the 3/10/12 aged.

Gender

Gender may influence the efficiency of biotransformation for specific xenobiotics. This is usually limited to hormone related differences in the oxidizing cytochrome P-450 enzymes. Important in various animal species but are seldom important in human beings.
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Interaction with food

Gastrointestinal absorption is favored by an empty stomach while absorption rate is reduced after ingestion of food. But still the nature of drug-food interactions is complex and unpredictable. However rate and extent of absorption of certain antibiotics is reduced after meals. Absorption of tetracycline is reduced if taken with milk or milk products (forms poorly absorbed complex with calcium ions) Vitamin C keeps iron in its ferrous form and therefore 3/10/12 increases its bioavailability

Food may interact with drugs, either:

Directly

Chemically i.e. chelation Physically i.e. by adsorbing the drug or acting as a barrier to absorption.

Indirectly - through physiological changes in GI tract like:

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gastric emptying is delayed

Effect of Food on Drug Absorption

Reduced absorption Ampicillin Aspirin Penicillins Tetracycline Ethanol Delayed absorption Diclofenac Digoxin Furosemide Sulfadiazine Increased absorption Diazepam Metoprolol Riboflavin Griseofulvin

Acetaminophen Hydralazine

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Drug Drug interactions

Antacids containing Al, Ca and Mg and haematinics containing iron causes reduced bioavilability of Tetracycline. Because the resultant chelated complex is poorly absorbed. Barbiturates reduce BA of several drugs due to enzymatic induction. Probenecid 3/10/12 blocks Penicillin excretion and thus enhances its BA.

Fluid volume

The volume of fluid with which an orally administered dose is taken can also affect a drug's bioavailability. Drug administration with a larger fluid volume will generally improve its dissolution characteristics and may also result in more rapid stomach emptying. Thus, more efficient and more reliable drug absorption can 3/10/12 be expected when an oral dosage form is administered with a larger volume of fluid.

Methods of assessing bioavailability

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Demonstration of a clinically significant effect

such clinical studies are complex, expensive, time consuming and require a sensitive and quantitative measure 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 a particular drug concentration at the site of action However, monitoring of pharmacologic data is often difficult, precision and reproducibility are 3/10/12

Urinary excretion data

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

These studies are based on the premise that urinary excretion of the unchanged drug is directly proportional to the plasma concentration of total drug. Thus, the total quantity of drug excreted in the urine is a reflection of the quantity of drug absorbed from the gastrointestinal tract.

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This technique of studying bioavailability is most useful for those drugs that are not extensively metabolized prior to urinary elimination.

As a rule-of-thumb, determination of bioavailability using urinary excretion data should be conducted only if at least 20% of a dose is excreted unchanged in the urine after an IV dose. In practice, these estimates are subject to a high degree of variability, and are less reliable than those obtained from plasma concentration-time profiles. Thus, urinary excretion of drug is not recommended as a substitute for blood concentration data; rather, these studies should be used in conjunction with blood level data for confirmatory purposes. 3/10/12

Blood level studies

most common type of studies based on assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action. Following the administration of a single dose of a medication, blood 3/10/12

1. AUC The area under the plasma concentration-time curve

The AUC is proportional to the total amount of drug reaching the systemic circulation. It is used to quantitate the extent of drug absorption.
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i.e.

Cmax is proportional to the rate of absorption 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 3/10/12

Bioequivalence

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The absence of a significant difference in the rate and extent to which the drug(active ingredient) in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of action when administered at same molar dose under similar conditions.
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Pharmaceutical equivalents drug products that contain identical amounts of identical active ingredients i.e. same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients. e.g. Diclofenac sodium Tablet Tablet 3/10/12 50mg 50mg

Diclofenac sodium

Pharmaceutical alternatives drug products that contain identical therapeutic moiety but not necessarily in the same amount or dosage form or as the same salt or ester. e.g. Diclofenac sodium Diclofenac sodium Tablet Capsule
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Questions..?

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