bio equivalence .pdf

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BIOAVAILABILITY AND
BIOEQUIVALENCE…

Methods of Assessing Bioavailability…
Different methods are used to assess drug
bioavailability:
I. Pharmacokinetic methods
 Plasma drug concentration data
 Urinary drug excretion data
II. Pharmacodynamic methods
 Acute pharmacodynamic effect
III. Clinical observation
IV. In vitro studies
Decreasing
accuracy and
preference
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Pharmacokinetic Methods…
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Urinary Drug Excretion Data
 The assessment of bioavailability by urinary excretion is based on
the assumption that the appearance of the drug in the urine is a
function of the rate and extent of absorption
 This assumption is only valid when a drug is extensively excreted
in the urine,
 rate of urinary excretion is proportional to the concentration of
the intact drug in the blood plasma

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Urinary Drug Excretion Data…
 The three major parameters examined in urinary excretion
data obtained with a single dose study are:
 The cumulative amount of drug excreted in the urine (D∞
u)
 The rate of drug excretion (dDu/dt)
 The total time for the drug to be excreted (t ∞)

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 The the cumulative amount of intact drug excreted (D∞
u):
 D∞
u is related directly to the total amount of drug absorbed
 urine samples are collected periodically after administration
of a single dose of a drug product
 each urine specimen is analyzed for free drug using a
specific assay
 A D∞
u curve is constructed that relates D∞
u to the collection-
time interval
 it is related to the AUC of plasma level data and increases
as the extent of absorption increases

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 Urine samples must be collected until all drug has been
excreted
 the cumulative urinary excretion curve becoming parallel to
the X-axis

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 The initial segments (X-Y) of the curves reflect the absorption
phase
 The total amount of intact drug excreted in the urine at point Z
corresponds to the time at which the plasma concentration of
intact drug is zero and
 essentially all the drug has been eliminated from the body

 The rate of drug excretion (dDu/dt)
 (dDu/dt ) represents urinary excretion rate
 (dDu/dt )max: The maximum urinary excretion rate,
 the maximum rate of drug excretion is at point Y,
 Its value increases as the rate of and/or extent of
absorption increases
 minimum rate of drug excretion is at points X and Y
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 The total time for the drug to be excreted (t ∞)
 point Z is related to the total time for the drug to be
absorbed and completely excreted t = ∞
 The t∞ is a useful parameter in BE studies that compare
several drug products

Fig.: Corresponding plots relating the
plasma level–time curve and the
cumulative urinary drug excretion.
(dDu/dt)max
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Fig: Corresponding plots relating the
plasma level–time curve and the rate of
urinary drug excretion

Acute pharmacodynamic effect
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 In some cases, the quantitative measurement of a drug in
plasma or urine lacks an assay with sufficient accuracy and/or
reproducibility
 For locally acting drug products e.g. topical corticosteroids,
plasma drug concentrations may not reflect the BA of the drug
at the site of action
 Thus, an acute pharmacodynamic effect approach may be
particularly applicable to dosage forms that are not
intended to deliver the active moiety to the bloodstream

Acute pharmacodynamic effect…
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 The use of an acute pharmacodynamic effect to determine BA
requires demonstration of a dose–response curve
 BA is determined by characterization of the dose–response
curve

Acute pharmacodynamic effect…
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 For bioequivalence determination, pharmacodynamic
parameters including
 Maximum pharmacodynamic effect (Emax)
 Time for maximum pharmacodynamic effect
 Area under the pharmacodynamic effect–time curve
 Onset time for pharmacodynamic effect

Acute pharmacodynamic effec…
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Acute pharmacodynamic effect–time curve.

Drug Product Indication Endpoint
Acarbose tablet type 2
diabetes
Reduction in blood glucose
concentrations
Orlistat capsules Treatment of obesity Amount of fat excreted
in feces over 24 hours
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Acute pharmacodynamic effec…
Ex. of Drug Products for which FDA Recommends BA studies using Pharmacodynamic
effect

In-Vitro Studies
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 Drug dissolution studies may give an indication of drug
bioavailability
 Ideally, the in-vitro drug dissolution rate should correlate with
in-vivo drug bioavailability
 Dissolution studies are often performed on several test
formulations of the same drug
 The formulation that demonstrates the most rapid rate of drug
dissolution will generally have the most rapid rate of drug BA

Bioequivalence Studies
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 BE studies are performed to compare BA of generic drug product
to brand-name product
 BE is established if the in-vivo BA of a test drug product does not
differ significantly in the product's rate and extent of drug
absorption, as determined by comparison of measured
parameters i.e.
 concentration of the active drug ingredient in the blood,
 urinary excretion rates, or
 pharmacodynamic effects from that of the reference drug

Bioequivalence Studies…
 BE studies require cooperative input from pharmacokineticists,
statisticians, clinicians, bioanalytical chemists, and others
 Once BE is established, it is likely that both the generic and
brand-name DFs will produce the same therapeutic effect
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Bioequivalence Studies: Design
 The design of the study should minimize the variability that is
not caused by formulation effects and eliminate bias as far
as possible
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Bioequivalence Studies: Design…
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 Appropriate study protocol including the required number of
subjects and sampling intervals should be determined
according to preliminary studies and previously reported
data
 There are various types of study design

1. Parallel group design
 Two formulations are administered to two separate groups of
volunteers
 To avoid bias, formulations may be administered randomly to
volunteers
 Disadvantage: inter-subject variation isn’t being corrected
 Most of the time, inter-subject variation is greater than variation
between formulations
 Substantially greater number of subjects are needed
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2. Crossover Designs
 each subject receives the test drug product and the reference
product
 Minimizes substantial inter-subject variability in study by using
 each subject as his own control
A. Latin-square crossover design
 Each subject receives each formulation only once with adequate
time between medications for elimination of drug
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Period 2
Washout
(passive) period
Period 1
Sequence
Test product
>5 half-lives
Reference
product
Sequence 1 (AB)
(n subjects)
Reference
product
Test product
Sequence 2 (BA)
(n subjects)
 A two-period, two sequence, single dose, cross-over, randomized
design in healthy volunteers

Group Subjects Period 1 Period 2
1 1 - 6 A B
2 7 – 12 B A
 Complete cross-over study of two products A and B in 12 subjects
 Period: time period in which study is performed
 Sequence: refers to the number of different orders in the
treatment groups in a study
 two-period, two-sequence study
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Advantages
1. Minimizes inter-subject variability in study
 Each subject serves as his own control
2. Minimizes carryover effect
 All subjects don’t receive same drug product on same day and
in same order
3. Requires less number of subjects to get meaningful results
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Disadvantages
1. Requires longer time to complete since washout period exists
between study periods
 Longer biological half-life
2. Time to complete trial depends on number of formulations
evaluated in study
3. Increased number of study periods leads to high subject
dropouts
4. Biomedical ethics doesn’t allow too many trials on subject
continuously for longer time
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B. Replicated Crossover Designs
 Replicated crossover designs are used for drug product containing
drug that has high intra-subject variability
 The same reference and the same test are each given twice to the
same subject
 reference-to-reference and test-to-test comparisons may also
be made
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B. Replicated Crossover Designs…
 Generally, a four-period, two-sequence, two-formulation
design is recommended by the FDA
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Study condition
 test conditions should be standardized in order to minimize
variability of all factors involved except that of products being
tested
 Standardization of diet, fluid intake and exercise is
recommended
 Different studies may be required for solid oral DFs
(1) Fasting study
(2) Food intervention study
(3) Multiple dose (steady-state) study
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Study condition…
Fasting Study
 required for all immediate-release and modified-release oral DFs
 subjects should be in the fasting state (overnight fast of at least 10
hrs) before drug administration and should continue to fast for up to
4 hrs after dosing
 Blood sampling is performed just before (zero time) the dose and at
appropriate intervals after the dose to obtain an adequate
description of the plasma drug concentration–time profile
 No other medication is given to the subject for at least 1 week prior
to the study
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Study condition…
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Food Intervention Study
 Co-administration of food with an oral drug product may
affect the bioavailability of the drug
 Food effect studies are generally conducted using meal
conditions that are expected to provide the greatest effects on
GI physiology
 systemic drug availability is maximally affected
 The test meal is a high-fat and high-calorie meal

Study condition…
Food Intervention Study…
 Following an overnight fast of at least 10 hrs, subjects are given the
recommended meal 30 min before dosing.
 The meal is consumed over 30 min, with administration of the
drug product immediately after the meal
 Drug product is given with 240 mL (8 fluid ounces) of water.
 No food is allowed for at least 4 hrs post dose
 This study is required for
 all modified-release DFs
 immediate-release DFs if the BA is known to be affected by food (eg,
Ibuprofen, Naproxen)
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Study condition…
Multiple-Dose (Steady-State) Study (read)
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Biopharmaceutics Classification
System (BCS)

Biopharmaceutics Classification System (BCS)…
 BCS attempts to classify drugs in terms of their aqueous
solubility and membrane permeability
 predict most likely behaviour of drug with regard to absorption
 BCS takes into account three major factors that govern rate
and extent of drug absorption from immediate release solid
oral DFs
 Dissolution,
 Solubility and
 Permeability
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 Drugs are classified into four classes according to their
solubility across the GI pH range and their permeability across
the GI mucosa
 The four classes are:
 Class I: high solubility/high permeability
 Class II: low solubility/high permeability
 Class III: high solubility/low permeability
 Class IV: low solubility/low permeability
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Class Solubility Permeability Comments
Class 1 High High Drug dissolves rapidly and is well absorbed. BA
problem is not expected for immediate release drug
products
Class 2 Low High Drug is dissolution limited and well absorbed. BA is
controlled by the DF and rate of release of the drug
substance
Class 3 High Low Drug is permeability limited. BA may be incomplete if
drug is not released and dissolved within absorption
window
Class 4 Low Low Difficulty in formulating a drug product that will
deliver consistent drug BA. An alternate route of
administration may be needed
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