1.
By
SURYAKANT VERMA,
Assistant Professor,
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BIOAVAILABILITY,
BIOEQUIVALENCE

2.
Bioavailability
Objectives of bioavailability
Factors effecting bioavailability
Measurement of bioavailability
Bioequivalence
Terms to know in Bioequivalence
Types of Bioequivalence studies
Acknowledgement
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3.
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4.
Regulatory Definition (21 CFR 320.1(a)):
“ Bioavailability-
means the rate and extent to which the
active ingredient or active moiety is absorbed
from a drug product and becomes available at
the site of action."
Or
“Bioavailability is defined as rate and extent
of absorption of unchanged drug from it’s
dosage form and become available at the site
of action.” 4

5.
Primary stages of development of a suitable dosage
form for new drug entity.
Determination of influence of excipients, patient related
factors and interaction with other drugs on the
efficiency of absorption.
To evaluate the absolute systemic availability of active
drug substance from a dosage form.
Control quality of drug in early stages of development.
Develop new formulation for existing drug.
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6.
Systemic availability the amount that reaches
systemic circulation is simply known as availability.
Absolute bioavailability of a drug product may be
comparing the respective bioavailabilites after an
oral and iv bolus injection.
Relative bioavailability is defined as a ratios of
bioavilabilities of a drug product and reference
standard.
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7.
Absolute bioavailability
Relative bioavailability
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8.
Route Bioavailability (%) Characteristics
Intravenous (IV) 100 (by definition) Most rapid onset
Intramuscular (IM) 75 to ≤ 100 Large volumes often possible;
may be painful
Subcutaneous (SC) 75 to ≤ 100 Smaller volumes than IM; may
be painful
Oral (PO) 5 to < 100 Most convenient; first pass
effects may be significant
Rectal (PR) 30 to < 100 Less first-pass effects than oral
Inhalation 5 to < 100 Often very rapid onset
Trans-dermal 80 to ≤ 100 Usually very slow absorption;
used for lack of first-pass
effects; prolonged duration of
action.

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Three major factors that effecting bioavailability:-
1. Pharmaceutical factors
2. Patient related factors
3. Routes of administration.

10.
Bioavailability
Pharmaceutical
Factors
Physicochemical
Factors
Pharmaco-
Technical
Factors
PatientRelated
Factors
Route Of
Administration
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11.
1.Pharmaceutical factors:
 Physicochemical properties of the drug.
1. Particle size
2. Crystalline structure
3. Salt form
 Pharmaco - Technical Factors or Formulation
and manufacturing variables.
1.Disintegration and dissolution time
2.Pharmaceutical ingredients
3.Special coatings
4.Nature and type of dosage form
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12.
2. Patient related factors:
 Physiologic factors.
1.Variations in pH of GI fluids
2.Gastric emptying rate
3. Intestinal motility
4. Pre-systemic and first-pass metabolism
5. Age, sex
6. Disease states
 Interactions with other substances.
1. Food
2. Fluid volume
3. Other drugs
3. Route of administration:
1.Parentral administration
2.Oral administration
3.Rectal administration
4.Topical administration 0

13.
The methods available are:-
Pharmacokinetic (Indirect) Method
Pharmacodynamic (Direct) Method.
Selection of method depends upon :-
Nature of The Study
Nature of Dosage Form
Analytical Method Development.
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14.
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Bio
availability
Indirect
methods
Plasma
data
T maxT max
C max
AUC
Urinary
data
dx u/dt
AUC
Xu
(T u ) Max
Direct
methods
Acute
pharmacolog
ical response
Clinical
response
(d Xu/dt ) Max

15.
Widely used and based on assumption that
Pharmacokinetic profile reflects the therapeutic
effectiveness of a drug.
Plasma Level- Time Studies:
Most common type of human bioavailability 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.
Following the administration of a single dose of a
medication, blood samples are drawn at specific time
intervals and analyzed for drug content.
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16.
A profile is constructed showing the concentration of
drug in blood at the specific times the samples were
taken.
Bioavailability (the rate and extent of drug
absorption) is generally assessed by the determination
of following three parameters.
They are..
1. Cmax (Peak plasma concentration)
2. Tmax (time of peak)
3. AUC (Area under curve)
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17.
Plasma Drug Concentration Vs Time Graph
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Cmax - Maximum plasma concentration.
1.The concentration of drug at therapeutic response is elicited.
2.Increase with increase in dose and with an increase in
absorption.
3.Expressed in terms of μg/ml or mg/ml.
Tmax-Time to reach maximum concentration
1.Indicates rate of absorption.
2.It decrease as the rate of absorption increases.
3.Expressed in terms of hours or minutes.
AUC - Area under thecurve.
1.Indicates the extent of drug absorption from a dosage form.
2.The fraction of dose that reaches the systemic circulation.
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 MEC: The minimum plasma concentration of the drug
required to achieve a given pharmacological or therapeutic
response.
 MSC: Plasma concentration of the drug beyond which
adverse effects are likely to happen.
 THERAPEUTIC RANGE: The range of plasma drug
concentration in which the desired response is achieved yet
avoiding adverse effect. The aim is clinical practice is to
maintain plasma drug concentration within the therapeutic
range.
 ONSET OF ACTION: On set of action is the time
required to achieve the minimum effective plasma
concentration following administration of drug formulation.19

20.
 DURATION OF ACTION- Duration of action of
the therapeutic effect of the drug is defined as the
time period during which the plasma concentration of
the drug exceeds the minimum effective level.
 INTENSITY OF ACTION- In general, the
difference between the peak plasma concentration
and the minimum effective plasma concentration
provides a relative measure of the intensity of the
therapeutic response of the drug.
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21.
The extent of bioavailability is
calculated from equation :
For single dose study:
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22.
Urinary Excretion Studies:
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, bioavailability can be
determined. eg: Thiazide diuretics, Sulphonamides.
Method is useful when there is lack of sufficiently
sensitive analytical technique to measure drug
concentration.
Noninvasive method, so better patient compliance.
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Rate of urinary excretion of drug versus time plot
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Maximum urinary excretion rate
• Its value increases as rate and/or extent of absorption increases.
• It is obtained from peak of plot between rate of urinary
excretion data versus time of urine collection period.
Time for maximum excretion rate
• It is the maximum time required to reach maximum excretion
rate.
• Its value decreases as absorption rate increases.
• Analogues of tmax of plasma level data.
Cumulative amount of drug excreted (X)u∞
• It is the drug excreted in urine till the drug level fallszero.
Related to AUC of plasma level data.
• It increases as the extent of absorption increases. 24

25.
The extent of bioavailability is calculated from
equation:
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26.
Sr. No Plasma data Urinary data
1. Maximum plasma
concentration
C max
Maximum urinary excretion
rate
2. Time to maximum
concentration
T max
Time to maximum
excretion rate
3. Area under the curve
AUC
Cumulative amount of drug
excreted
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Acute pharmacological response
When bioavailability measurement by pharmacokinetic
method is difficult, an acute pharmacologic effect are taken
into consideration.
Dose response curve Can be determined by construction of
Pharmacological effect Vs Timecurve.
E.g.: pupil diameter, heart rate or BP can be useful as an index
of drug Bioavailability.
Disadvantage:
• It tends to be more variable.
• Observed response may be due to an active metabolite
whose concentration is not proportional to concentration of
parent drug.
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29.
Clinical response / Therapeutic response
•Best method Clinical response of the drug for which it is
intended to be used is measured.
•Based on clinical response to the drug formulation given to
the patients
E.g.: for anti-inflammatory drugs, reduction in inflammation is
determined
Drawbacks:
The major drawbacks of this method is that quantitation of observed
response is too improper to allow for reasonable assessment of
relative bioavailability between two dosage forms of the same drug.
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Bioequivalence
When the drug from two or more similar dosage form
reaches the general circulation at the same relative rate
and extent then the dosage forms are termed as
Bioequivalent.
Statistical significant differences are observed in the
bioavailability of two or more drug products,
termed as Bio-inequivalence.
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32.
1. A comparison of the bioavailability of two or more
drug products.
2. Two products or formulations containing the same
active ingredient are bioequivalent if their rates and
extents of absorption are the same.
3. Bioequivalence may be demonstrated through in
vivo
or
in vitro test methods, comparative clinical trials, or
pharmacodynamic studies.
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0
10
20
30
40
50
60
70
80
90
0 10 20 30
Concentration(ng/mL)
Time(hours)
Test/Generic
Reference/Brand

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Bioequivalence: IR Products
Reference Test
Pharmaceutical Equivalent
Products
Possible Differences
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
(Note: Generally, same dissolution spec.)
Normal healthy subjects
Crossover design
Overnight fast
Glass of water
90% CI within 80-125%
of Ref. (Cmax & AUC)

35.
When significant changes are made in the manufacture of the
marketed formulation.
When a new generic formulation is tested against the
innovator's marketed product.
Comparison of availability of drug substance from different
dosage forms.
when changes in formulation have occurred after an
innovator product has been approved.
Comparison of availability's of same dosage formproduced
by different manufactures. 21

36.
Equivalence
Chemical equivalence
Clinical equivalence
Pharmaceutical Equivalence
Bioequivalence
Therapeutic equivalence
Comparable Dosage Form
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37.
Equivalence may be defined in several ways:
Chemical equivalence:
If two or more dosage forms of same drug contain same labeled
quantities specified in pharmacopoeia. Eg : Dilantin and Eptoin
chemically equivalent as they contain same quantity of
Phenytoin on chemical assay.
Bioequivalence:
The drug substance in two or more identical dosage forms,
reaches the systemic circulation at the same relative rate and
extent i.e. their plasma concentration-time profiles will be
identical without significant statistical differences.

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Pharmaceutical equivalents:
Drug products in identical dosage forms that contain same active
ingredient(s), i.e , the same salt or ester, are of the same dosage
form, use the same route of administration, and are identical in
strength or concentration.
Eg : Chlordiazepoxide hydrochloride,5mg capsules.
Pharmaceutical equivalent drug products are: Same in :
•Active ingredient and it’s quantity
•Dosage form
•Standards like strength, quality , purity and identity.
•Disintegration time
•Dissolution rates
Differ in:
•Shape
•Release mechanisms
•Packing
•Excipients(including colours , flavours , preservatives)
•labeling

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Pharmaceutical alternatives:
•Drug product that contain the same therapeutic moiety but as
different salts, esters or complexes.
Eg: Tetracyclin phosphate or Tetracyclin hydrochloride equivalent to
250mg.
Therapeutic equivalents:
•Drug products consider to be therapeutic equivalence only if they are
pharmaceutical equivalence and if they can be expected to have a
same clinical effect and safety profile when administered to patient
specified in the labeling.
•FDA classifies as therapeutically equivalent those products that meet
the fallowing general criteria:
1)They approved as safe and effective.
2)They are pharmaceutically equivalents.
3)They are bioequivalence.
4)They are adequately labeled .
5)They are manufactured in compliance with current GMP regulations.

40.
Therapeutic alternatives:
•Drug products containing different active ingredients that are
indicated for the same therapeutic or clinical objectives.
Eg:
1. Ibuprofen is given instead of Aspirin.
2. Cimetidine instead of Ranitidine.
Therapeutic substitution:
•The process of dispensing a therapeutic alternative in place of
the prescribed drug product.
Eg:
1. Ampicillin is dispensed instead of Amoxicillin.
2. Ibuprofen is dispensed instead of Naproxen.

41.
Bioequivalence
studies
In vivo
Oral immediate
release
Non oral
immediate
release
Modified
release with
systemic action
In vitro
Clinical studies
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