Bioavailability: by Abera J

Bioavailability
By; Abera J
Definition
Bioavailability
• Is defined as the rate and extent of absorption of
unchanged drug from its DF.

• Also refers to the extent and speed with which the
active part (drug or metabolite) enters the

systemic circulation, accessing the site of
action.
Definition…
Bioequivalent drug products
Describes that the drug substance in two or more identical
DFs, reaches the systemic circulation at the same relative
rate and to the same relative extent
i.e. their plasma concentration-time profiles will be
identical without significant statistical differences.

Definition…
Pharmaceutical substitution
The process of dispensing a pharmaceutical alternative
for the prescribed drug product.
For example,
Ampicillin suspension is dispensed in place of ampicillin
capsules, or TTC hydrochloride is dispensed in place of
TTC phosphate.
Pharmaceutical substitution generally requires the

physician's approval.
Definition…
Therapeutic alternatives
Drug products containing different AIs that are indicated
for the same therapeutic or clinical objectives.
AIs in therapeutic alternatives are from the same

pharmacologic class and are expected to have the same
therapeutic effect when administered to Pts.
For example,
Ibuprofen is given instead of ASA; cimetidine may be

given instead of ranitidine.
Definition…
Therapeutic substitution
The process of dispensing a therapeutic alternative
in place of the prescribed drug product.
For example,
Amoxicillin is dispensed instead of ampicillin or

ibuprofen is dispensed instead of naproxen.
Definition…
Therapeutic equivalents
Drug products are considered to be therapeutic

equivalents only if;
They are pharmaceutical equivalents and if
they can be expected to have the same
clinical effect and safety profile when
administered to Pts
Definition…
The FDA classifies as therapeutically equivalent those
products that meet the following general criteria:
They are approved as safe and effective;
They are pharmaceutical equivalents
They are bioequivalent
They are adequately labeled; and
They are manufactured in compliance with Current

GMP regulations.
Purpose of BA Studies
BA studies are performed for both approved AIs and

therapeutic moieties not yet approved for marketing by
the FDA.
New formulations of AIs must be approved by the FDA
before marketing.
In approving a drug product for marketing,
The FDA ensures that the drug product is safe and
effective for its labeled indications for use.
Purpose of BA Studies…
Moreover,
The drug product must meet all applicable
standards of identity, strength, quality, and
purity.
To ensure that these standards are met,
The FDA requires BA/PK studies and, where
necessary, bioequivalence studies for all drug
products.
BA studies are one of the factors that link in-vivo

performance of the drug product used in clinical
studies;
For determination of evidence of safety and efficacy.
BA studies provide useful information important to
establish dosage regimen and to support
drug labeling.
BA studies help in determining;

The influence of excipient, Pt related factors and
possible interaction with other drugs on the efficiency of
absorption.
BA studies estimates the quality control of a drug
product during the early stages of marketing;
So that the influence of processing factors, storage
and stability on drug absorption can be determined.
Types of BA
BA fraction (F) is a term which refers to the fraction

of administered dose that enters the systemic
circulation and can be calculated as:
BA of a drug depends upon mainly three major factors.

1. Pharmaceutical factors including physiochemical
factors and formulation factors.
2. Pt related factors.
3. Route of drug administration.
Types of BA…
The area under the drug concentration–time curve (AUC);

Is used as a measure of the total amount of
unaltered drug that reaches the systemic circulation.
The AUC is dependent on;
The total quantity of available drug (FD0), divided
by the elimination rate constant (k), and the
apparent volume of distribution ( VD).

Types of BA…
F is the fraction of the dose absorbed;

After IV administration, F is equal to unity, because the
entire dose enters the systemic circulation.
Therefore, the drug is considered to be completely

available after IV administration.
After PO administration of a drug;
F may vary from 0 to 1;
0 (no drug absorption) to 1 (complete drug
absorption).
Absolute BA
The absolute BA of drug is the systemic availability of
a drug after extravascular administration (PO, rectal,
transdermal, SC) compared to IV dosing.
The absolute BA of a drug is generally measured by
comparing the respective AUCs after extravascular and
IV administration.
Absolute availability, F, may be expressed as a fraction or as a percent by multiplying F x 1
Absolute availability, F, may be expressed as a fraction or as a percent by multiplying F x
Absolute BA…
This measurement may be performed as long as VD and k are
independent of the RA.
Absolute BA after PO drug administration using plasma
data can be determined as follows:
Absolute BA may be expressed as a fraction or as a

percent by multiplying F x 100.
Absolute BA…
Significance of absolute BA
The drug is completely BA when F=l, for the drugs

given by IV injection.
F<l is for the drugs which are poorly absorbed or
metabolized by first pass effect.
Example: Insulin solution shows zero BA as it is
extensively degraded in GI tract.
Relative BA
Relative BA is a measure of the given dug absorbed

systematically after PO administration compared with
that of PO standard of the same drug
Example
Comparison between Amoxicillin capsule and
Amoxicillin suspension.
Where drug product B is the recognized reference standard.
This fraction may be multiplied by 100 to give percent.

Relative BA…
When different doses are administered;
A correction for the size of the dose is made, as
in the following equation:

Practice Problem
The BA of a new investigational drug was studied in
12 volunteers. Each volunteer received either a single
oral tablet containing 200mg of the drug, 5mL of a
pure aqueous solution containing 200mg of the
drug, or a single IV bolus injection containing
50mg of the drug. Plasma samples were obtained
periodically up to 48hours after the dose and assayed
for drug concentration.
Practice Problem…
The average AUC values (0–48 hours) are given in the
table below.
Practice Problem…
From these data, calculate;
a) The relative BA of the drug from the tablet

compared to the oral solution and
b) The absolute BA of the drug from the tablet.
Solution
The relative BA of the drug from the tablet;
Relative BA = (AUC)tablet/(AUC)solution
= 89.5/86.1
= 1.04 =104%
The relative BA of the drug from the tablet is 1.04, or 104%,
compared to the solution.
In this study, the difference in drug BA between tablet and
solution was not statistically significant.
It is possible for the relative BA to be greater than 100%.
Solution…
The absolute drug BA from the tablet;
Absolute BA = (AUC)PO*IV dose/(AUC)IV*PO Dose
= 89.5*50/37.8*200
= 4475/7560
= 0.5919*100
= 59.19% = 59.2%
Because F, the fraction of dose absorbed from the tablet, is
less than 1, the drug is not completely absorbed systemically,
As a result of either poor absorption or metabolism by first-
pass effect.
Methods for Assessing BA
Direct and indirect methods may be used to assess

drug BA.
The in-vivo BA of a drug product is demonstrated by the
rate and extent of drug absorption, as determined by
comparison of measured parameters,
Example: Concentration of the AI in the blood, cumulative
urinary excretion rates, or pharmacological effects.
Methods for Assessing BA…
For drug products that are not intended to

be absorbed into the bloodstream,
BA may be assessed by measurements
intended to reflect the rate and extent to
which the AI becomes available at the
site of action.
The design of the BA study depends on;

The objectives of the study,
The ability to analyze the drug (and metabolites)

in biological fluids,
The PD of the drug substance,
The route of drug administration, and
The nature of the drug product.
PKs methods: These are indirect methods

based on the assumption that PKs profile
reflects the therapeutic effectiveness of a
drug.
The two major PKs methods are:
1. Plasma level time profile;
I. Time for peak plasma concentration (tmax)
II. Peak plasma drug concentration (Cmax)
III. AUC
2. Urinary excretion data;

I. Cumulative amount of drug excreted in the
urine (Dt)
II. Rate of drug excretion in the urine —Du dt
III. Time for maximum urinary excretion (t)

PD methods: These involve direct measurement of

pharmacologic or therapeutic end point.
The two PD methods of BA determination involve;
1. Acute pharmacologic response
I. Maximum PD effect (Emax)

II. Time for maximum PD effect
III. Area under the PD effect time curve

IV. Onset time for PD effect
2. Therapeutic response/Clinical Observation
Pharmacokinetic Method
1. Plasma drug concentration
Most common type of human BA studies.

Based on the 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.
Pharmacokinetic Method…
1. Plasma drug concentration…

Following the administration of a single dose of a
medication,
blood samples are drawn at specific time
intervals and analyzed for drug content.
Requires collection of serial blood sample after
drug administration
Plasma drug concentration is plotted against time.
Figure-1: A typical plasma concentration-time profile showing PK
and PD parameters obtained after PO administration of a single
dose of a drug

a. Time for peak plasma concentration (tmax)
Time at which the maximum plasma concentration, (Cp)
max is achieved after drug administration.
At tmax, rate of absorption is equal to the rate of
elimination.
After tmax is reached, drug absorption still continue
but at slow rate.
It is expressed in hours, tmax indicates drug absorption rate.

b) Peak plasma drug concentration (Cmax)
It is the maximum plasma drug concentration

achieved after drug administration.
Indicates that drug is absorbed systemically and
therapeutic response is obtained.
Expressed in μg/ml or mg/ml.
Figure-2: Plasma drug concentration–time curve

c. AUC
It is measurement the extent of drug absorption.
Indicates the amount of AI that reaches systemic

circulation.
AUC not depends on RA.
If the drug is following linear kinetics,

Then AUC is directly proportional to the dose,
Inversely proportional to the clearance of the drug.

Relationship between AUC and Dose
Figure-3: Linear relationship between AUC and dose

Reading Assignment
Methods used to determine AUC;
Cut and Weight Method
By using Planimeter
Trapezoidal method
2. Urinary drug excretion data

Sometimes it is not possible to collect blood samples,
but one may be able to estimate the amount of

drug excreted unchanged into the urine.
Under these conditions, urinary excretion data
become more appropriate for PKs studies.
2. Urinary drug excretion data…

Urinary excretion of unchanged drug is directly
proportional to plasma concentration of drug.
Thus, even if a drug is excreted to some extent (at least
10 to 20%) in the urine, BA can be determined.
eg: Thiazide diuretics, Sulphonamides.
2. Urinary drug excretion data…
Useful when there is lack of sufficiently sensitive
analytical technique to measure drug concentration.
Non-invasive method, so better Pt compliance

Pharmacodynamic Methods
These methods are used when BA measurement by
PK method is difficult or giving non reproducible
data
Acute PD effect
Clinical Observations
Pharmacodynamic Methods…
Acute PD effects
In some cases, the quantitative measurement of a drug
in plasma or urine lacks an assay with sufficient
accuracy or reproducibility.
For locally acting, nonsystemically absorbed drug
products,
such as topical corticosteroids, plasma drug
concentrations may not reflect the BA of the drug at the
site of action.
Acute PD effects…
An acute PD effect,
such as an effect on FEV1 (inhaled bronchodilators)

or skin blanching (topical corticosteroids) can be
used as an index of drug BA.
In this case, the acute PD effect is measured over a
period of time after administration of the drug product.
Acute PD effects…
This approach may be particularly applicable to DFs
that are not intended to deliver the active moiety
to the bloodstream for systemic distribution.
The use of an acute PD effect to determine BA generally
requires demonstration of a dose–response curve.
BA is determined by characterization of the dose–
response curve.
Clinical Observations
Well-controlled clinical trials in humans establish
the safety and effectiveness of drug products and
may be used to determine BA.
However, the clinical trials approach is the least
accurate, least sensitive, and least reproducible of
the general approaches for determining in-vivo BA.
Clinical Observations…
The FDA considers this approach only;
When analytical methods and PD methods are not
available to permit use of one of the approaches
described above.
BA Enhancement of Poorly Soluble Drugs
There are different methods which are used to
overcome the BA problem;
Enhancement of drug solubility
Enhancement of drug permeability
Enhancement of drug stability

Enhancement of drug solubility
Particle size reduction
There is a direct r/ship b/n the SA of the drug and
its rate of dissolution.
As the SA increases with decreasing particle size,
higher dissolution rates can be achieved
Particle size reduction results better dissolution
and BA.
Enhancement of drug solubility…
Use of surfactant
Surfactant enhances both dissolution rate and

permeability of drug.
They enhance dissolution rate primarily by promoting
wetting and penetration of dissolution fluid into the
solid drug particle.
BA of steroids like spironolactone drugs have been
increased by use of surfactant.
Use of cosolvents
The solubility of a poorly water soluble drug can

be enhanced by the addition of a water miscible
solvent or cosolvents.
Cosolvents are mixtures of water and one or
more water miscible solvents,
Used to increase the solubility for poorly
soluble compounds.
Use of Salt forms

Salt has improved solubility and dissolution
characteristics
Alkyl metal salt of acidic drugs like Penicillin and
strong acid salts of basic drugs like atropine are
more water soluble than the parent drug.
Enhancement of Drug Permeability
Lipid Technologies
Lipid base formulations have been designed to improve the
BA by various mechanisms like;
Reduction in GET by increasing the time available for
dissolution and absorption
Increased intestinal membrane permeability
Increased intestinal blood flow
Increased luminal degradation
Increased uptake from the intestinal lumen in to the
lymphatic system.
Enhancement of Drug Permeability…
Ion pairing
This approach involves co-administration of a
hydrophilic or polar drug with a suitable lipophilic
counter ion,
Which improves the partitioning of the resultant

ion pair into the intestinal membrane.
Ion pairing increases the oral BA of the ionizable

drug by two folds.
Enhancement of Drug Permeability…
Penetration enhancer
Acts by interaction its lipid part with the polar
component of membrane phospholipids.
Facilitate the transport of drug across the membrane.

This method is used for hydrophilic drugs which
have difficulty in penetrating the liquid structure of
the membrane.
E.g.: Fatty acids, salicylates, Ethylenediamine tetraacetic
acid (EDTA) etc.
Enhancement f Drug Stability
Enteric Coating……..…this technique retards the release of drug

in stomach.
Example: Erythromycin, Penicillin-V etc.
Complexation………….this technique is used to increase the
stability of drug in GIT.
Examples: ester drugs thus enhance their BA.
Use of metabolism Inhibitor……….metabolism inhibitor
selectively inhibits any of the contributing processes
which would result in increased fractional absorption and
enhance the BA.
THANK YOU.

Bioavailability: by Abera J

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Bioavailability

unchanged drug from its DF.

active part (drug or metabolite) enters the

Bioequivalent drug products

Describes that the drug substance in two or more identical

DFs, reaches the systemic circulation at the same relative

rate and to the same relative extent

i.e. their plasma concentration-time profiles will be

identical without significant statistical differences.

Pharmaceutical substitution generally requires the

AIs in therapeutic alternatives are from the same

Ibuprofen is given instead of ASA; cimetidine may be

Amoxicillin is dispensed instead of ampicillin or

Drug products are considered to be therapeutic

They are manufactured in compliance with Current

BA studies are performed for both approved AIs and

BA studies are one of the factors that link in-vivo

BA studies help in determining;

BA fraction (F) is a term which refers to the fraction

BA of a drug depends upon mainly three major factors.

The area under the drug concentration–time curve (AUC);

The AUC is dependent on;

The total quantity of available drug (FD0), divided

by the elimination rate constant (k), and the

apparent volume of distribution ( VD).

F is the fraction of the dose absorbed;

Therefore, the drug is considered to be completely

The absolute BA of drug is the systemic availability of

a drug after extravascular administration (PO, rectal,

transdermal, SC) compared to IV dosing.

The absolute BA of a drug is generally measured by

comparing the respective AUCs after extravascular and

This measurement may be performed as long as VD and k are

independent of the RA.

Absolute BA after PO drug administration using plasma

data can be determined as follows:

Absolute BA may be expressed as a fraction or as a

The drug is completely BA when F=l, for the drugs

Relative BA is a measure of the given dug absorbed

Where drug product B is the recognized reference standard.

This fraction may be multiplied by 100 to give percent.

When different doses are administered;

A correction for the size of the dose is made, as

in the following equation:

a) The relative BA of the drug from the tablet

Direct and indirect methods may be used to assess

For drug products that are not intended to

The design of the BA study depends on;

The ability to analyze the drug (and metabolites)

PKs methods: These are indirect methods

2. Urinary excretion data;

III. Time for maximum urinary excretion (t)

PD methods: These involve direct measurement of

I. Maximum PD effect (Emax)

III. Area under the PD effect time curve

1. Plasma drug concentration

Most common type of human BA studies.

1. Plasma drug concentration…

1. Plasma drug concentration…

1. Plasma drug concentration…

It is the maximum plasma drug concentration

1. Plasma drug concentration…

It is measurement the extent of drug absorption.