Pharmacology bioavailability

1. Bioavailability
By : Aditya Arya

2. •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:

3. 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.

4. 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

6. Pharmacokinetic Studies
Key Measurements
•AUC
–Area under the concentration-
time curve
•C
max
–Maximum concentration
–A difference of greater than
20% in C
max or the AUC
represents a significant
difference between the study
and reference compounds
•T
max
–Time to maximum
concentration
Study Compound
Reference Compound
Time
C
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C
max
T
max
AUC

7. FDA Requirements for
Bioequivalence
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
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8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. Volume of Distribution :
The volume of distribution (V
D
) , 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.

14. 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.

15. Distribution of drug in the absence of elimination:
The apparent volume into which a drug distributes, V
D
, 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. 

16. 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 V
D
 for that drug 
is known. 
The V
D
 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.

17. For example :
If 25 mg of a drug (D = 25 mg) are 
administered and the plasma 
concentration is 1 mg/L, then 
       V
D
 = 25 mg/1 mg/L = 25 L.

19. 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.

21. 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 C
0
, 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 C
0
 = 1 mg/L  and then 
V
D
 = 10 mg/1 mg/L = 10 L.

23. 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, V
d
 
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 C
1
 and the desired level of digitalis (known from clinical 
studies) is a higher concentration, C
2
. The clinician needs to know how 
much additional drug should be administered to bring the circulating 
level of the drug from C
1
 to C
2
:
  The difference between the two values is the 
additional dosage needed, which equals V
D
(C
2
  C
1
).

24. 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

25. Concept of “Half Life”
Time [hours]
0 4 8 12 16 20 24
C
o
n
c
.

[
m
g
/
L
]
0
1
2
3
4
5

27. Dependence of Half-life on
Clearance and Volume

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

29. 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

30. The V
D
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:

V
P
= plasma volume
V
T
= apparent tissue volume
fu = fraction unbound in plasma
fu
T
= fraction unbound in tissue

31. 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

32. Dose regimen Response Exposure
Site of action
Pharmacokinetics Pharmacodynamics

33.  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)
General Outline

35. 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

36. 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
Dosing
Sampling at
Pre-determined
Time intervals
Bio-analytics
Conc. vs time
profiles
Blood withdrawal

37. Concentration versus Time Profiles
One-
Compartment
Model
Assumes body as one
compartment
1
Two-Compartment Model
Central compartment (drug entry and
elimination)
Tissue compartment (drug distributes)
1 2
k
k
Dose
Dos
e
Broadly the concentration – time profiles can be viewed as two different ways

38. 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

39. Concept of “Half Life”
Time [hours]
0 4 8 12 16 20 24
C
o
n
c
.

[
m
g
/
L
]
0
1
2
3
4
5

41. Dependence of Half-life on
Clearance and Volume

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

43. 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

44. Time [hours]
0 4 8 12 16 20 24
C
o
n
c
.

[
m
g
/
L
]
0
1
2
3
4
5
Time [hours]
0 4 8 12 16 20 24
C
o
n
c
.

[
m
g
/
L
]
0
1
2
3
4
5
Solution
Capsule
20 mg administered as
an i.v. bolus (Diovan)
80 mg given as a solution
and a capsule (Diovan)

46. Thank you