Pharmacology bioavailability

Bioavailability By : Aditya Arya

• 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:

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.

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

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

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

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ange

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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

Concept of “Half Life”

Time [hours]

0 4 8 12 16 20 24

Co

nc.

[mg

/L]

0

1

2

3

4

5

Dependence of Half-life on Clearance and Volume

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

clearance

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

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

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

Dose regimen Response ExposureSite of action

Pharmacokinetics Pharmacodynamics

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

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

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

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

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

Concept of “Half Life”

Time [hours]

0 4 8 12 16 20 24

Co

nc.

[mg

/L]

0

1

2

3

4

5

Dependence of Half-life on Clearance and Volume

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

clearance

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

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)

Thank you