Bioavailability

By : Aditya Arya

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.

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 Studies
Key Measurements
Study Compound
Reference Compound

Concentration

Cmax

AUC
Tmax

Time

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

FDA Requirements for

Bioequivalence

Pharmacokinetic
Reference Range

125%

100%

80%
Product A
Bioequivalent

Reference
Drug

Product B
Not 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

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).

Concept of Half Life

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 life
distribution life = when plasma levels fall to
half what they were at equilibrium due to
distribution to/storage in bodys tissue reservoirs
elimination life = when plasma levels fall to
half what they were at equilibrium due to drug
being metabolized and eliminated
It is usually the elimination 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

5

C o n c . [m g /L ]

0
0

12

Time [hours]

16

20

24

Dependence of Half-life on
Clearance and Volume

For a given dose rate, the blood drug

concentration is inversely proportional to
clearance

Bioavailability and Its Assessment

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)

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 volume
VT = apparent tissue volume
fu = fraction unbound in plasma
fu = fraction unbound in tissue

 Pharmacokinetics
what the body does to the
drug
Absorption
Distribution
Metabolism
Elimination

disposition

Pharmacodynamics
what the drug does to the
body
wanted effects - efficacy
unwanted effects toxicity

Pharmacokinetics

Dose regimen

Exposure

Pharmacodynamics

Site of action

Response

General Outline
Basic Pharmacokinetic Concepts
Bioavailability
Definition
How absorption affects bioavailability?
Food Effect
How drug metabolism affects bioavailability?
How transporters affect bioavailability?

Bioequivalence
Definition
Bio-IND
Waivers of In Vivo Study Requirements
Biopharmaceutics Classification System (BCS)

Basic Concepts
Easy to understand using intravenous
route
No absorption phase
Simple to follow
Concepts clear with less
assumptions

Drug
Product

Drug in
Blood

Excretion

Distribution to
Tissue and Receptor sites

Metabolism

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.

IV administration,
contd.,

Following dose administration,

we need to follow its drugs
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 ConcentrationTime profile

Dosing

Sampling at
Pre-determined
Time intervals

Blood withdrawal

Bio-analytics

Conc. vs time
profiles

Concentration versus Time Profiles

Broadly the concentration time profiles can be viewed as two diffe

One-Compartment
Model

Dose

Assumes body as one compartment

Two-Compartment
Model
Central compartment (drug entry
and elimination)
Tissue compartment (drug
distributes)

Dos
e

Concept of Half Life

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 life
distribution life = when plasma levels fall to
half what they were at equilibrium due to
distribution to/storage in bodys tissue reservoirs
elimination life = when plasma levels fall to
half what they were at equilibrium due to drug
being metabolized and eliminated
It is usually the elimination 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

5

C o n c . [m g /L ]

0
0

12

Time [hours]

16

20

24

Dependence of Half-life on
Clearance and Volume

For a given dose rate, the blood drug

concentration is inversely proportional to
clearance

Bioavailability and Its Assessment

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)

Conc. [mg/L]

Conc. [mg/L]

Solution
Capsule

0
0

12

16

20

24

Time [hours]

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

12

16

20

24

Time [hours]

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

Thank you