BA and BE studies

BIOAVAILABILITY & BIOEQUIVALENCE
STUDIES
UNDER THE GUIDANCE OF : PRESENTED BY :
Prof . R. NAGARAJU M.HARITHA
Institute of Pharmaceutical Technology,
Sri Padmavati Mahila Visvavidyalayam
( Women’s University)
Tirupati. A.P
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 Bioavailability is a term used to indicate the Fractional extent to
which a dose of drug reaches to its site of action or a biological
fluid, from which the drug has access to its site of action.
OR
 It is defined as an Rate and Extent of absorption of unchanged
drugs from its dosage form.
BIOAVAILABLE FRACTION:
Bioavailable dose
F =
Administered dose
BIOAVAILABILITY :

CONSIDERATIONS IN IN-VIVO BIOAVAILABILITY
STUDY DESIGN :
 There are 2 types of bioavailability
1) Absolute Bioavailability
2) Relative Bioavailability
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Absolute Bioavailability :
When the systemic availability of the drug after oral
administration is compared to its IV administration is called as
Absolute Bioavailability.
Absolute bioavailability after oral drug administration using
plasma data can be determined as following :
(AUC)oral
F =
(AUC)iv
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 It is used to characterize a drug inherent absorption
properties from the extravascular site.
EXAMPLE :
Absolute Bioavailability of Nimodipine for different
route of administration
Oral – 1.17%
Nasal – 67.4 %
IV - 100%
An Absolute Bioavailability of 1 or 100 % indicates complete
absorption by comparing reference standard as an IV dose.
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 F may be expressed as fraction ( or ) as percentage multiplying
F*100 absolute availability using urinary excretion data can be
determined.
(Du)oral dose oral
F =
(Du)iv dose iv
Du = Total amount of drug excreted in urine.
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RELATIVE BIOAVAILABILITY:
When the systemic availability of the drug after oral
administration is compared with that of oral standard of same
drug (such as aqueous or non aqueous solutions , suspensions)
is referred as relative or comparative bioavailability.
It is used to characterize absorption of drug from its
formulation.
(AUC) A
Fr =
(AUC)B
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EXAMPLE:
 Comparision between Capsule Amoxicillin & Suspension
Amoxicillin.
When different doses are administered a correction for the size
of dose is made , as the following equation.
(AUC)A dose A
Relative availability =
(AUC) B dose B
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 The total amount of drug excreted in the urine is collected as
the percentage availability using urinary excretion data can be
determined as follows
% Relative availability = { (Du)A/ (Du) B }
Relative bioavailability 1or 100 % indicates that bioavailability
of drug from both dosage forms is same but does not indicates
complete absorption.
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BIOEQUIVALENCE STUDIES
DEFINITION :
It refers to the drug substance in two or more
identical dosage forms, reaches systemic circulation at the same
rate to the relative extent.
i.e. their plasma concentration time profiles will be
identical without significant statistical difference.
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ADVANTAGES:
 Minimizes the effect of inter subject variability.
 It minimizes the carry over effect.
 Requires less number of subjects to get meaningful results.
 DISADVANTAGES:
 Requires long time to complete the studies.
 Increase in study periods leads to high subject dropouts.
 Completion of studies depends on number of formulations evaluated in
the studies.
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OBJECTIVES:
 If a new product is intended to be substitute for an approves
medicinal product as a pharmaceutical equivalent or alternative
,equivalence with this product should be shown or justified.
 Bioequivalence studies are conducted if there is :
 A risk of bio inequivalence and /or
 A risk of pharmacotherapeutic failure or diminished clinical safety.
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Some of the important terms relevant in this context
will be defined.
 Equivalence: It is a relative term that compares drug product with
respect to a specific characteristic or function to defined set of
standards.
 There are several types of equivalences:
A. Chemical Equivalence
B. Pharmaceutical Equivalence
C. Bioequivalence
D. Therapeutic Equivalence
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Types of Bioequivalence Studies
 Bioequivalence can be demonstrated either:
 In vivo or
 In vitro
IN VIVO
1. Oral immediate release products with systemic action-
Indicated for serious conditions requiring assured response.
Narrow therapeutic margin.
Unfavorable physicochemical properties eg. Low solubility ,
metastable modifications.
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 Non – oral immediate release products.
 Modified release products with systemic action.
 In vivo bioequivalence studies are conducted in the usual
manner i.e pharmacokinetic & pharmacodynamic methods.
 PHARMACOKINETIC METHODS
a) Plasma level time studies
b) Urinary Excretion studies
 PHARMACODYNAMIC STUDIES
a) Acute pharmacological response
b) Therapeutic response
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In vitro Bioequivalence studies
 The drug product differs only in strength of active substance it
contains some of the following conditions :
a) Pharmacokinetics are linear
b) The qualitative composition is the same.
c) The ratio between the active substances and the
excipients is the same.
d) Both products are produced by the same
manufacturer at the same production site.
e) The product contains active ingredient in the same
concentrations as the approved drug product.
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 The drug product meets all the following requirements:
a) The product is in the form of solution or solubilized form.
b) The product contains active ingredient in the same
concentration as the approved drug product.
 The drug product has been slightly reformulated or the
manufacturing method has been slightly modified by the
original manufacturers.
 An acceptable IVIVC and the invitro dissolution rate of new
product is equivalent with that of already approved medicinal
product.
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DESIGN OF BIOEQUIVALENCE STUDIES:
P
R
O
T
O
C
O
L
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Analytical Methods
 Must be accurate
 Should be with appropriate precision
 Measure the actual concentration of the active drug or active
metabolites achieved in the body.
REFERENCE STANDARD
 Reference standard is generally a formulation currently
marketed with a fully approved NDA for which there are valid
scientific safety and efficacy data.
 Usually innovators or brand drug.
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EXTENDED RELEASE FORMULATIONS:
 Product has claimed controlled release characters
 No occurrence of dose dumping.
 Steady state is equivalent to currently marketed extended release
formulation.
COMBINATION OF DRUG PRODUCTS
 To determine the rate & extent of absorption of each active
ingredient administered concurrently as separate single ingredient
preparations.
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STUDY DESIGNS
 Fasting study
 Food intervention study
 Multiple - dose
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FASTING STUDY
 Done for immediate release and modified release oral dosage forms
 Male and female subjects may be used
 Blood sampling is done at appropriate intervals to obtain plasma
drug concentration- time profile.
 Subjects should be fasting condition – at least 10 hours before
drug administration and 4 hours after administration
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FOOD INTERVENTION STUDY
These studies are conducted after high fat & high calorie meal.
 Meal is given 30 minutes before dosing.
 No food is given for at least 4 hours after administration.
 Done for modified release dosage forms.
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MULTIPLE - DOSE
 Done for extended release drug products
 Done in addition to the fasting & food intervention study
Sampling done similar to fasting study.
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CROSS OVER DESIGNS
Each subject receives the test & reference drug product.
 Eg : Latin square designs
 Each subject receives only one drug product
 Adequate wash-out periods is provided between drugs.
 ADVANTAGES:
 Subject – to – subject variation is reduced
 All patients don ot receive same drug product on the same day.
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 PERIOD-time period in which a study is performed
 Two period study- performed on 2 different days separated by a
washout period – generally 10 elimination half lives.
SEQUENCE – no.of different orders in the treatment groups in
a study
 For eg: two sequence , two period study would be designed as
follows
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EVALUATION DATA
 1.ANALYTICAL METHOD
 Must be validated for accuracy, precision , sensitivity& specifity
 Using more than one analytical method for a study is not valid –
different methods may yield different results.
 Plasma concentration - time curve should be available.
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2.PHARMACOKINETIC EVALUATION OF DATA
 Area under curve to the last quantifiable concentration ( AUC0-t)
 Area under curve to infinity ( AUC0-∞)
 Tmax
 C max
 Elimination rate constant ,k
 Elimination half –life t1/2
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STATISTICAL EVALUATION OF DATA
 ANALYSIS OF VARIANCE (ANOVA)
 When Dp <0.05, the difference between 2 drug product is not
“statistically significant”
 TWO ONE SIDED TESTS PROCEDURE
 Demonstrate if bioavailability of the drug from test formulation is
too low or high or in comparison to reference drug
 Evaluation of confidence limits – 90% ± 20%
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CONCLUSION:
 Concept of bioequivalence has been adopted by the
pharmaceutical industry and national regulatory authorities
through out the world for over 20 years.
There is continuing attempt to understand & develop more
sufficient & scientifically valid approaches to assess
bioequivalence of various dosage forms including some of the
tough complex special dosage forms.
 Absolute & Relative biaoavailability shows drug availability
according to their standards
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REFERENCES
 Lachmann / Lieberman’s, The theory and practice of
industrial pharmacy.
 Brahmankar DM, Jaiswal SB, Biopharmaceutics and
Pharmacokinetics..
 www.google.com
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