B I OAVA I L A B I L I T Y
&
B IO E Q U IVAL E N C E
Prof. Dr. Fatima Tawfiq
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DEFINITIONS
• Bioavailability - rate and extent at which therapeutically active drug
reaches systemic circulation.
• Bioequivalence - the fact when two pharmaceutical equivalents have
similar bioavailability; the meaning of ‘similar’ depends on the
concrete case
• ◦ in most cases it means similar rate and extent of absorption
• ◦ sometimes only extent
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• Pharmaceutical equivalent
• same active ingredient (same salt form)
• same amount of active ingredient
• same dosage form
• inactive ingredients can be different
• Therapeutic equivalents
• pharmaceutical equivalents that produce the same effects in patients
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• Pharmaceutical alternative
• same active ingredient (salt form can be different)
• amount of active ingredient can be different
• dosage form can be different
• inactive ingredients can be different
• Therapeutic alternatives
• ◦ drug products containing different active ingredients that are indicated for
the same therapeutic or clinical objective
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• Generic substitution
• The process of dispensing drug product with the same active ingredient and similar
bioavailability made by different manufacturers in place of the prescribed drug
• Pharmaceutic substitution
• The process of dispensing a pharmaceutical alternative in place of prescribed drug
• Therapeutic substitution
• The process of dispensing a therapeutic alternative in place of prescribed drug
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• Brand name.
• The trade name of the drug. This name is privately owned by the
manufacturer or distributor and is used to distinguish the specific drug
product from competitor's products (eg, Tylenol, McNeil Laboratories).
• Chemical name.
• The name used by organic chemists to indicate the chemical structure of the
drug (eg, N-acetyl-p-aminophenol).
• Generic name
• established, nonproprietary, or common name of the drug (acetaminophen)
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New Drug - NDA
Generic Product – ANDA
• A new drug has to prove efficacy & safety (NDA)
• A generic product of an existing drug has to be bioequivalent to the brand
(reference) product by demonstrating the same in vivo (absorption)
performance (ANDA)
• Absolute availability - for drugs with approved NDA, bioavailability studies
are required for new drug formulations - bioequivalence to the reference
formulation
• Relative availability - for drugs without full NDA, bioequivalence to the
reference drug in the standard formulation
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Bioavailability (F)
• ‘‘The relative amount of an administered dose that reaches the
general circulation and the rate at which this occurs’’ (American
Pharmaceutical Association, 1972)
• Bioavailability indicates a measurement of the rate and extent
(amount) of therapeutically active drug which reaches the general
circulation.
• Bioavailability captures two essential features, namely how fast the
drug enters the systemic circulation (rate of absorption) and how
much of the nominal strength enters the body (extent of absorption)
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• Given that the therapeutic effect is a function of the drug
concentration in a patient's blood, these two properties of non-
intravenous dosage forms are, in principle, important in identifying
the response to a drug dose:
1. Onset of response is linked to the rate of drug absorption whereas the
time-dependent
2. Extent of response is linked to the extent of drug absorption.
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Drug Bioavailability Process
Drug in the drug product
Solid drug particles
Drug in solution
Drug in the body
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• Bioavailability following oral doses may vary because of either
patient-related or dosage-form-related factors
• Patient factors can include the nature and timing of meals, age,
disease, genetic traits and gastrointestinal physiology
• The dosage form factors include 1) the chemical form of the drug
(e.g. salt vs. acid), 2) its physical properties (e.g. crystal structure,
particle size), and 3) an array of formulation (e.g. non-active
ingredients) and manufacturing (e.g. tablet hardness) variables
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Bioavailability studies importance:
• In the strict sense, bioavailability studies provide an estimate of the
fraction of the orally administered dose that is absorbed into the
systemic circulation when compared to the bioavailability for a
solution or intravenous dosage form that is completely available
• Bioavailability studies provide other useful information that is
important to establish dosage regimens and to support drug
labeling, such as distribution and elimination characteristics of the
drug
• Bioavailability studies provide indirect information regarding the
presystemic and systemic metabolism of the drug and the role of
transporters such as p-glycoproteins
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• Bioavailability studies designed to study the food effect provide
information on the effect of food and other nutrients on the
absorption of the drug substance
• Such studies when designed appropriately provide information on the
linearity or nonlinearity in the pharmacokinetics of the drug and the
dose proportionality
• Bioavailability studies provide information regarding the performance
of the formulation and subsequently are a means to document
product quality
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Absolute bioavailability
• Absolute availability is determined for the same drug in various
formulations
• Absolute bioavailability of a drug is the systemic availability of the
drug after extravascular administration of the drug and is measured
by comparing the area under the drug concentration–time curve after
extravascular administration to that after IV administration
• Extravascular administration of the drug comprises routes such as
oral, rectal, subcutaneous, transdermal, nasal, etc.
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IV bolus
100
Concentration 80
60
40
20
0
0 5 10 15 20 25 30
Time
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Oral dosage form (product A
100
80
Area under concentration
Concentration
curve (AUC)
60
40
20
0
0 5 10 15 20 25 30
Time
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Absolute bioavailability
100 For the same dose
(IV vs. Oral), the
80
bioavailability is given
Concentration
60
by:
40 AUCoral DOSEiv
F=
20
AUCiv DOSEoral
0
0 5 10 15 20 25 30
Time
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Where 𝐷𝑢 is the total amount of drug excreted in the
urine
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Relative bioavailability
• Relative availability is determined for various drugs
• The relative bioavailability is the systemic availability of a drug from
one drug product (A) compared to another drug product (B).
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Oral dosage form (product A)
100
80
Concentration
60
40
20
0
0 5 10 15 20 25 30
Time
20
Oral dosage form (product B)
100
80
Concentration
60
40
20
0
0 5 10 15 20 25 30
Time
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Relative bioavailability
100
For the same dose
(Oral vs. Oral), the
80 bioavailability is given
by:
Concentration
60
F= AUC oral ( A)
40
AUCoral
20
( B)
0
0 5 10 15 20 25 30
Time
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Example
• The bioavailability of a new investigational drug was studied in 12
volunteers. Each volunteer received either a single oral tablet
containing 200 mg of the drug, 5 mL of a pure aqueous solution
containing 200 mg of the drug, or a single IV bolus injection
containing 200 mg of the drug. The average AUC values are given in
the table below. From these data, calculate
• the relative bioavailability of the drug from the tablet compared to the oral
solution
• the absolute bioavailability of the drug from the tablet
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• F= 50/75 = 0.667 or 66.67%
• F= AUC oral X Dose iv
AUC iv Dose oral
= 50 X 200
150 200
= 0.333 0r 33.3%
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Factors affecting bioavailability
1.Presystemic and systemic metabolism — Presystemic metabolism,
which occurs during first-pass metabolism, can decrease the
bioavailability of a drug. The following types of metabolism are
commonly seen:
• First-pass metabolism: First-pass metabolism occurs when an absorbed drug passes directly
through the liver before reaching systemic circulation after oral administration.
• Intestinal metabolism: Drug metabolizes in the intestine itself or during the passage
through the intestinal wall.
• Hydrolysis of the drug in the stomach fluids.
• Transporters such as p-glycoprotein may influence the bioavailability of a drug.
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Factors affecting bioavailability
2.Gastric emptying: Although not true in all cases, increased gastric
emptying generally enhances bioavailability of orally administered
drugs. Gastric emptying depends on the following factors:
• Volume of liquid intake
• Volume of solid food intake and its fat content
• Viscosity of stomach content
• pH of the stomach
• Intake of other drugs
• Age and weight of the patients
• Physical activity of the patients taking drug
• Emotional state of the patient
• Various disease states
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3. Complexation with other agents in the gastrointestinal tract
4. Formulation factors, such as may occur with inert ingredients, the
manufacturing process and/or use of surfactants, etc
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Causes of poor of bioavailability:
• The major causes of poor of bioavailability:
• Poor aqueous solubility and/or slow dissolution rate in biological fluid.
• Poor stability of the dissolved drug at the physiologic pH.
• Inadequate partition coefficient and thus poor permeation through the
biomemberane.
• Extensive presystemic metabolism.
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Approaches in overcoming the bioavailability
problems
• There are three major approaches in overcoming the bioavailability problems due
to such causes are:
• The pharmaceutic Approach: which involve a modification of formulation,
manufacturing process or the physicochemical properties of the drug without changing
the chemical structure.
• The pharmacokinetic approach: in which pharmacokinetic of drug can altered by
modifying in chemical structure.
• The biologic approach: which can change the route of administration
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Bioequivalence
• A bioequivalence study is a specialized type of relative bioavailability
study.
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• Bioequivalent drug products. This term describes pharmaceutical
equivalent or pharmaceutical alternative products that display
comparable bioavailability when studied under similar experimental
conditions. For systemically absorbed drugs, the test (generic) and
reference listed drug (brand-name) shall be considered
bioequivalent if:
• the rate and extent of absorption of the test drug do not show a
significant difference from the rate and extent of absorption of the
reference drug when administered at the same molar dose of the
therapeutic ingredient under similar experimental conditions in
either a single dose or multiple doses
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Methods to Assess Bioavailability and
Bioequivalence
1 Plasma drug concentration
• Time for peak plasma (blood) concentration (t max)
• Peak plasma drug concentration (C max)
• Area under the plasma drug concentrationan time curve (AUC)
• Example: In vivo: whole blood, plasma, serum
• Method of evaluation of free drug in systemic
circulation
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• AUC: Trapezoidal Rule
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Methods to Assess Bioavailability and
Bioequivalence
2 Urinary drug excretion
• Cumulative amount of drug excreted in the urine (Du)
• Rate of drug excretion in the urine (dD u/dt)
• Time for maximum urinary excretion (t)
• Method of evaluation of Elimination
The relationship between the cumulative amount of drug
excreted in the urine and the plasma level– time curve. When
the drug is almost completely eliminated, the plasma
concentration approaches zero and the maximum amount
of drug excreted in the urine, Du∞, is obtained.
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Methods to Assess Bioavailability and
Bioequivalence
3 Acute pharmacodynamic effect
• Maximum pharmacodynamic effect (E max)
• Time for maximum pharmacodynamic effect
• Area under the pharmacodynamic effect of time curve
• Onset time for pharmacodynamic effect
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Methods to Assess Bioavailability and
Bioequivalence
4 Clinical observations
• Well-controlled clinical trials
• Observed clinical success or failure
• Example: In vivo: evaluation of clinical response
5 In-vitro studies
• Drug dissolution
• Method of evaluation: Dissolution rate
• Example: In vitro: water, buffer, artificial gastric fluid, artificial intestinal
fluid, artificial saliva, artificial rectal fluid.
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BIOWAIVER
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• the BCS was developed for regulatory applications: to provide a basis
for replacing, in certain cases, in vivo BE studies by equally or more
accurate in vitro tests.
• biowaiver: an acceptance for replacing an in vivo BE study with in
vitro dissolution testing.
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Class I Class II
High solubility Low solubility
High permeability High permeability
Class III Class IV
High solubility Low solubility
Low permeability Low permeability
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According to BCS, in vivo bioavailability and bioequivalence studies
need not be conducted for drug products under following
circumstances
• Rapid and similar dissolution.
• High solubility.
• High permeability.
• Wide therapeutic window.
• Excipients used in dosage form are same as those present in approved
drug product
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Example
The data in the table represent the average findings in antibiotic
plasma samples taken from 10 humans (average weight 70 kg).
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a.Which of the four drug products would be preferred as a reference standard
for the determination of relative bioavailability?Why?
b.From which oral drug product is the drug absorbed more rapidly?
c.What is the absolute bioavailability of the drug from the oral solution?
d.What is the relative bioavailability of the drug from the oral tablet
compared to the reference standard?
Answers:
a: Oral solution, because the drug is in the most bioavailable form
b: oral solution, same reason above
c: absolute bioavailability = (145/10) / (29/2) = 1
d: Relative bioavailability = (116/10) / (145/10) = 0.8
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