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Bioavailabil ity By : Aditya Arya

Pharmacology bioavailability

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Page 1: Pharmacology   bioavailability

Bioavailability By : Aditya Arya

Page 2: Pharmacology   bioavailability

• Bioavailability is the fraction of administered drug that reaches the systemic circulation.

• Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form.

• For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent.

Bioavailability:

Page 3: Pharmacology   bioavailability

Determination of bioavailability:

Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection in which all of the agent rapidly enters the circulation.

When the drug is given orally, only part of the administered dose appears in the plasma.

Page 4: Pharmacology   bioavailability

By plotting plasma concentrations of the drug versus time, we can measure the area under the curve (AUC).

This curve reflects the extent of absorption of the drug. [Note: By definition, this is 100 percent for drugs delivered IV.]

Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection

Page 5: Pharmacology   bioavailability
Page 6: Pharmacology   bioavailability

Pharmacokinetic StudiesKey Measurements

• AUC– Area under the concentration- time

curve

• Cmax

– Maximum concentration– A difference of greater than 20% in

Cmax or the AUC represents a significant difference between the study and reference compounds

• Tmax

– Time to maximum concentration

Study CompoundReference Compound

Time

Con

cent

ratio

n

Cmax

Tmax

AUC

Page 7: Pharmacology   bioavailability

FDA Requirements for Bioequivalence

125%

100%

80%

Product ABioequivalent

Reference Drug

Product BNot Bioequivalent

• Product A is bioequivalent to the reference drug; its 90% confidence interval of the AUC falls within 80% to 125% of the reference drug

• Product B is not bioequivalent to the reference drug; its 90% confidence interval of the AUC falls outside of 80% to 125% of the reference drug

Phar

mac

okin

etic

Ref

eren

ce R

ange

Page 8: Pharmacology   bioavailability

Factors that influence bioavailability:

First-pass hepatic metabolism: When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation.

If the drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased. Many drugs, such as propranolol or lidocaine, undergo significant biotransformation during a single passage through the liver.

Page 9: Pharmacology   bioavailability

Solubility of the drug:

Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes.

For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions. This is one reason why many drugs are weak acids or weak bases. There are some drugs that are highly lipid-soluble, and they are transported in the aqueous solutions of the body on carrier proteins such as albumin.

Page 10: Pharmacology   bioavailability

Chemical instability:

Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes.

Nature of the drug formulation:

Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption.

Page 11: Pharmacology   bioavailability

Bioequivalence:

Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Two related drugs with a significant difference in bioavailability are said to be bioinequivalent.

Page 12: Pharmacology   bioavailability

Therapeutic equivalence :

Two similar drugs are therapeutically equivalent if

they have comparable efficacy and safety.

Clinical effectiveness often depends on both the

maximum serum drug concentrations and on the

time required (after administration) to reach peak

concentration. Therefore, two drugs that are

bioequivalent may not be therapeutically

equivalent.

Page 13: Pharmacology   bioavailability

Volume of Distribution :The volume of distribution (VD) , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing. It is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.

Volume of distribution may be increased by renal failure (due to fluid retention) and liver failure (due to altered body fluid and plasma protein binding ). Conversely it may be decreased in dehydration.

Page 14: Pharmacology   bioavailability

Volume of distribution may be increased by renal

failure (due to fluid retention) and liver

failure (due to altered body fluid and plasma

protein binding. Conversely it may be decreased

in dehydration.

Page 15: Pharmacology   bioavailability

Distribution of drug in the absence of elimination:

The apparent volume into which a drug distributes, VD, is determined by injection of a standard dose of drug, which is initially contained entirely in the vascular system. The agent may then move from the plasma into the interstitium and into cells, causing the plasma concentration to decrease with time. Assume for simplicity that the drug is not eliminated from the body; the drug then achieves a uniform concentration that is sustained with time. The concentration within the vascular compartment is the total amount of drug administered, divided by the volume into which it distributes.

Page 16: Pharmacology   bioavailability

Apparent volume of distribution : total amount of drug in the body VD = ---------------------------------------------- drug blood plasma concentration

Therefore the dose required to give a certain plasma concentration can be determined if the VD for that drug is known.

The VD is not a physiologic value; it is more a reflection of how a drug will distribute throughout the body depending on several physicochemical properties, e.g. solubility, charge, size, etc.

Page 17: Pharmacology   bioavailability

For example :

If 25 mg of a drug (D = 25 mg) are administered and the plasma concentration is 1 mg/L, then

VD = 25 mg/1 mg/L = 25 L.

Page 18: Pharmacology   bioavailability
Page 19: Pharmacology   bioavailability

Distribution of drug when elimination is present:

In reality, drugs are eliminated from the body, and a plot of concentration versus time shows two phases. The initial decrease in plasma concentration is due to a rapid distribution phase in which the drug is transferred from the plasma into the interstitium and the intracellular water. This is followed by a slower elimination phase during which the drug leaves the plasma compartment and is lost from the body

For example, by renal or biliary excretion or by hepatic biotransformation. The rate at which the drug is eliminated is usually proportional to the concentration of drug, C; that is, the rate for most drugs is first-order and shows a linear relationship with time if ln C (where ln C is the natural log of C, rather than C) is plotted versus time . This is because the elimination processes are not saturated.

Page 20: Pharmacology   bioavailability
Page 21: Pharmacology   bioavailability

Calculation of drug concentration if distribution is instantaneous:

Assume that the elimination process began at the time of injection and continued throughout the distribution phase. Then, the concentration of drug in the plasma, C, can be extrapolated back to time zero (the time of injection) to determine C0, which is the concentration of drug that would have been achieved if the distribution phase had occurred instantly.

For example, if 10 mg of drug are injected into a patient and the plasma concentration is extrapolated to time zero, the concentration is C0 = 1 mg/L and then VD = 10 mg/1 mg/L = 10 L.

Page 22: Pharmacology   bioavailability
Page 23: Pharmacology   bioavailability

Uneven drug distribution between compartments:

The apparent volume of distribution assumes that the drug distributes uniformly, in a single compartment. However, most drugs distribute unevenly, in several compartments, and the volume of distribution does not describe a real, physical volume, but rather, reflects the ratio of drug in the extraplasmic spaces relative to the plasma space. Nonetheless, Vd

is useful because it can be used to calculate the amount of drug needed to achieve a desired plasma concentration. For example, assume the arrhythmia of a cardiac patient is not well controlled due to inadequate plasma levels of digitalis. Suppose the concentration of the drug in the plasma is C1 and the desired level of digitalis (known from clinical

studies) is a higher concentration, C2. The clinician needs to know how

much additional drug should be administered to bring the circulating level of the drug from C1 to C2:

The difference between the two values is the additional dosage needed, which equals VD(C2 C1).

Uneven drug distribution between compartments:

The apparent volume of distribution assumes that the drug distributes uniformly, in a single compartment. However, most drugs distribute unevenly, in several compartments, and the volume of distribution does not describe a real, physical volume, but rather, reflects the ratio of drug in the extraplasmic spaces relative to the plasma space. Nonetheless, Vd

is useful because it can be used to calculate the amount of drug needed to achieve a desired plasma concentration. For example, assume the arrhythmia of a cardiac patient is not well controlled due to inadequate plasma levels of digitalis. Suppose the concentration of the drug in the plasma is C1 and the desired level of digitalis (known from clinical

studies) is a higher concentration, C2. The clinician needs to know how

much additional drug should be administered to bring the circulating level of the drug from C1 to C2:

The difference between the two values is the additional dosage needed, which equals VD(C2 C1).

Page 24: Pharmacology   bioavailability

Concept of “Half Life” ½ life = how much time it takes for blood levels of

drug to decrease to half of what it was at equilibrium

There are really two kinds of ½ life…“distribution” ½ life = when plasma levels fall to

half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs

“elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated

It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug

Page 25: Pharmacology   bioavailability

Concept of “Half Life”

Time [hours]

0 4 8 12 16 20 24

Co

nc.

[mg

/L]

0

1

2

3

4

5

Page 26: Pharmacology   bioavailability
Page 27: Pharmacology   bioavailability

Dependence of Half-life on Clearance and Volume

Page 28: Pharmacology   bioavailability

For a given dose rate, the blood drug concentration is inversely proportional to

clearance

Page 29: Pharmacology   bioavailability

Bioavailability: The rate and extent to which the parent compound reaches the general circulation.

Absolute Bioavailability

requires I.V. administration Ratio of the oral:intravenous AUC values normalized

for dose Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral)

Relative Bioavailability

no I.V. reference comparison AUC values (ratio) of different dosage

forms / formulations Frel = (AUC a / AUC b) * (Dose b /Dose a)

Bioavailability and Its Assessment

Page 30: Pharmacology   bioavailability

The VD may also be used to determine how readily a drug will displace into the body tissue compartments relative to the blood: VD = VP + VT ( fu / fuT )

Where:

VP = plasma volumeVT = apparent tissue volume fu = fraction unbound in plasma fuT = fraction unbound in tissue

Page 31: Pharmacology   bioavailability

Pharmacokinetics “what the body does to the

drug”• Absorption• Distribution• Metabolism• Elimination

Pharmacodynamics “what the drug does to the

body”• wanted effects -

efficacy• unwanted effects -

toxicity

disposition

Page 32: Pharmacology   bioavailability

Dose regimen Response ExposureSite of action

Pharmacokinetics Pharmacodynamics

Page 33: Pharmacology   bioavailability

Basic Pharmacokinetic Concepts

BioavailabilityDefinitionHow absorption affects bioavailability?Food EffectHow drug metabolism affects bioavailability?How transporters affect bioavailability?

BioequivalenceDefinitionBio-INDWaivers of In Vivo Study RequirementsBiopharmaceutics Classification System (BCS)

General Outline

Page 34: Pharmacology   bioavailability
Page 35: Pharmacology   bioavailability

Basic Concepts

Easy to understand using intravenous route

No absorption phase Simple to follow Concepts clear with less

assumptions

Need some math background algebra, log scale, Simple linear

Equations etc complex math (differential

equations, statistical concepts etc) for Modeling, Population PK, PK-PD etc.

Drug Product

Drug in Blood

Distribution to

Tissue and Receptor sites

MetabolismExcretion

Page 36: Pharmacology   bioavailability

IV administration, contd.,

Following dose administration, we need to follow its drug’s disposition to understand its PK characteristics.

This is achieved by analyzing the changes of the drug and/or its metabolite(s) in blood, plasma, urine etc.

A simple approach is to generate Drug Concentration-Time profile

DosingSampling at

Pre-determined

Time intervals

Bio-analytics Conc. vs time

profiles

Blood withdrawal

Page 37: Pharmacology   bioavailability

Concentration versus Time Profiles

One-Compartment Model Assumes body as one compartment

1

Two-Compartment ModelCentral compartment (drug entry and elimination)

Tissue compartment (drug distributes)

1 2

k

k

Dose

Dose

Broadly the concentration – time profiles can be viewed as two different ways

Page 38: Pharmacology   bioavailability

Concept of “Half Life” ½ life = how much time it takes for blood levels of

drug to decrease to half of what it was at equilibrium

There are really two kinds of ½ life…“distribution” ½ life = when plasma levels fall to

half what they were at equilibrium due to distribution to/storage in body’s tissue reservoirs

“elimination” ½ life = when plasma levels fall to half what they were at equilibrium due to drug being metabolized and eliminated

It is usually the elimination ½ life that is used to determine dosing schedules, to decide when it is safe to put patients on a new drug

Page 39: Pharmacology   bioavailability

Concept of “Half Life”

Time [hours]

0 4 8 12 16 20 24

Co

nc.

[mg

/L]

0

1

2

3

4

5

Page 40: Pharmacology   bioavailability
Page 41: Pharmacology   bioavailability

Dependence of Half-life on Clearance and Volume

Page 42: Pharmacology   bioavailability

For a given dose rate, the blood drug concentration is inversely proportional to

clearance

Page 43: Pharmacology   bioavailability

Bioavailability: The rate and extent to which the parent compound reaches the general circulation.

Absolute Bioavailability

requires I.V. administration Ratio of the oral:intravenous AUC values normalized

for dose Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral)

Relative Bioavailability

no I.V. reference comparison AUC values (ratio) of different dosage

forms / formulations Frel = (AUC a / AUC b) * (Dose b /Dose a)

Bioavailability and Its Assessment

Page 44: Pharmacology   bioavailability

Time [hours]

0 4 8 12 16 20 24

Con

c. [m

g/L]

0

1

2

3

4

5

Time [hours]

0 4 8 12 16 20 24

Con

c. [m

g/L]

0

1

2

3

4

5

SolutionCapsule

20 mg administered as an i.v. bolus (Diovan)

80 mg given as a solution and a capsule (Diovan)

Page 45: Pharmacology   bioavailability
Page 46: Pharmacology   bioavailability

Thank you