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1. BIOAVAILABILITY AND BIOEQUIVALENCE OF DRUG PRODUCT
SUBMITTED BY SUBMITTED TO –
Kritika Singh Mrs. Anupriya Adhikari Mam
ROLL NO - (Associate Proffessor)
220420801008
DATE OF SUBMISSION –
26 – MAY – 2023
M.PHARMA (PHARMACEUTICS)
(SECOND SEM)

2. INTRODUCTION
Bioavailability quantifies the proportion of a drug which is absorbed
and available to produce systemic effects .
 Bioavailability is a fundamental property of a pharmaceutical product
for a given route of administration.
 It should be known and shown to be reproducible for all drug
products intended to produce a systemic effects.
 Bioequivalence is a term in pharmacokinetics used to access the used
to access the expected in vivo biological equivalence of two
proprietary preparation of a drug.
 If two products are said to be bioequivalent it means that they would
be expected to be ,for all intents and purposes, the same.

3. DRUG PRODUCT PER
 Drug product performance , in vivo, may be defined as the release of
the drug substance from the drug product leading to bioavailability of
the drug.
 The assessment of drug product performance is important since
bioavailability is related both to the pharmacodynamic response and
to adverse events.
 Performance tests relate the quality of a drug product to clinical
safety and efficacy

4. BIOAVALABILITY
The term bioavailability is defined as a rate and extent (amount) of
absorption of drug from its dosage form

5. OBJECTIVES
• Entity Determination of influence of excipients patient related factors and
possible reaction with other drug on efficient of absorption.
 Primary stages of development of a suitable dosages form for a new drug
entity.
 Development of new formulation of existing drug.
 Control of quality of drug product during early marketing in order to
determine the influence of processing factors, storage and stability on
drug absorption.

6. CONSIDERATIONS IN BIOAVAILABILITY STUDY
DESIGN
Absolute bioavailability
“ When the systemic availability of a drug administered orally is
determined in comparison to its intravenous administration , is called as
absolute bioavailability “.
% Absorption = Dose (iv) * Dose ( oral ) * 100
Dose ( oral ) * Dose (iv)

7. Relative bioavailability
• When the systemic bioavailability of a drug after administered orally
is compared with that of an oral standard of the same drug ( aqueous
or non aqueous solutions ).
• It is denoted by symbol (Fr).
FR = [AUC] test D Std
[AUC] std D test
• It is used to characterize absorption of a drug from its formulation. F
and Fr are generally expressed in percentage (%).

8. • MEASUREMENT OF BIOAVAILABILITY
The methods available are classified as pharmacokinetic methods and
pharmacodynamic methods.
• Pharmacokinetic ( indirect )
1. Plasma level time studies
2. Urinary excretion studies
• Pharmacodynamic ( direct )
1. Acute pharmacological response
2. Therapeutic response

9. 1. Pharmacokinetics Method (Indirect)
a) Plasma Level Time Studies
• Plasma level time curve describes the situation of drug concentration in our body after administration with
time (specific time intervals).
• During clinical trials, the patient’s plasma drug concentration-time profile can be drawn by assessing the
plasma concentration at specific time points.
• By using appropriate blood sampling, an accurate description of the plasma drug concentration-time profile of
the pharmacologically active drug substance(s) can be achieved using a validated drug assay.
• The plasma level time curve is obtained by plotting the concentration of the drug in plasma after
administration of a drug (Y-axis) and the corresponding time at which the plasma sample was collected (X-
axis). IV Bolus vs IV Infusion
• Generally, plasma or serum is utilized the most frequently for direct drug measurement. A drug or drug product
enters the systemic circulation after delivery, and over time, plasma drug concentrations increase.
• The drug is distributed to the intracellular and extracellular regions of the body’s tissues from the systemic
circulation after absorption from the GIT, and it is also eliminated at the same time either by excretion,
biotransformation, or both processes. Plasma level time curve also known as plasma drug.

11. b) Urinary Excretion Study
• In a cumulative urinary excretion study, urine is collected upon administration of a drug product until the
unchanged drug is more or less excreted from the body (at least 7 ⋅ t1/2 when> 99% of the drug is eliminated).
• In each urine sample of a collecting period, the drug concentration per milliliter is determined.
• It is base on the principle that the urinary excretion of unchanged drug is directly proportional to plasma
concentration of drug .
Method
• Collection of urine at regular intervals for a time span equal to 7biological half life .
• Analysis of unchanged drug in collected sample and determined the amount of drug excreted in each interval
and cumulative amount excreted .
• At each sample collection , total emptying of the bladder is necessary to avoid errors resulting from additional
of residual amount to the next urine sample.

13. 2. Pharmacodynamics Method (Direct )
a) Acute pharmacological response
• When bioavailability measurement by pharmacokinetics method is difficult , inaccurate or non-
predictable , an acute pharmacological effect such as change in EEg or ECG reading , pupil diameter
etc.
• It is related to the time course of given drug bioavailability can then be determined by constriction of
pharmacological effect time curve as well as dose response graph.
• The method require measurement of response for at least 3 biological half live of the drug in order to
obtain a good estimation of AUC.
DISADVANTAGE
• The pharmacological response tends to be more variable and accurate correlation between measured
response and drug available from the formulation is difficult .

14. b) Therapeutic response
• Theoretically the most definite this method is based on observing the clinical response to the
drug formulation given to patient suffering diseases for which it is intend to be used.
DISADVANTAGE
 In that Quantization of observed response is too improper to allow for reasonable assessment of
relative bioavailability between two dosages forms of the same drugs.
 Many patients receive more than one drug, and the result obtained from a bioavailability study
could be compromised because of a Drug- Drug interaction.

15. BIOEQIVALENCE
• Therapeutic equivalence Two pharmaceutical products are therapeutically
equivalent if they are pharmaceutically equivalent and after administration
in the same molar dose their effects, with respect to both efficacy and safety,
will be essentially the same as can be derived from appropriate studies
(bioequivalence, pharmacodynamic, clinical or in-vitro studies).
• Therapeutically equivalent drug product are interchangeable.
Target of BA and BE study
• Bioavailability and Bioequivalence studies are required by regulations to
ensure therapeutic equivalence between a pharmaceutically equivalent test
drug and reference drugs.

16. CRITERIA FOR BIOEQUIVALENCE
• To establish bioequivalence , the calculated 90% confidence interval for AUC and
Cmax should fall with in the bioequivalence range , usually 80.00 – 125.00%.
• The non- parametric 90% confidence interval for T max should lie with in a
clinically acceptable range.
• Tighter limits for permissible differences in bioavailability may be required for
drug that have:
 A narrow therapeutic index
 A serious , dose – related toxicity
 A steep dose / effect curve
 A non linear pharmacokinetics with in the therapeutic dose range A wider
acceptance range may be acceptable if it is based on sound clinical justification.

17. DESIGN AND CONDUCT OF PHARMACOKINETIC STUDIES
a) Study Design
According to following points the design of an in vivo bioavailability study is determined :
 The nature of reference drug and the dosage form to be tested.
 Benefit risk ratio considerations in regard to testing in humans.
 The availability of analytical methods .
 What is the scientific questions to be answered
Single dose studies generally suffice . however situations as described below may demand a steady state study
design:
 Some modified release drugs

18. Selection of the number of subjects
The number of subjects required for should be statistically significant and is determined by the
following considerations:
 The level of significant should be 0.05.
 The error variance associate with the primary characteristics to be studies as estimated from a
pilot experiment, from previous studies.
 The expected deviation from the reference drug compatible with bioequivalence.
 The required power, normally > 80% to detect the maximum allowable difference in primary
characteristics to be studies.

19. Selection criteria for subjects
The studies should be normally performed on healthy adult volunteers with aim to
minimize variability and permit detection of differences between the study drugs.
Subjects may be males or
females; however the choice of gender should be consistent with usage and safety
criteria.
To minimize intra and inter individual variation subjects should be consistent with
usage and safety criteria.
Genetic phenotyping
Phenotyping and genotyping of subjects should be considered for exploratory
bioavailability studies and all studies using parallel group design.

20. Study Condition
Standardization of the study environment , diet , fluid intake, post dosing postures,
exercise, sampling schedules etc.
It is important in all studies.
Selection of Blood Sampling Schedules
The blood sampling period in single dose trials of an immediate release product should
extent to at least three elimination half lives.
Sampling should be continued for a sufficient period to ensure that the area extrapol -ated
from the time last measured concentration to infinite time only a small percentage of the
total AUC .
The use of a truncated AUC is undesirable except in certain circumstances such as in the
accurately.

21. For multiple dose fasting state studies, when an evening
dose must be given, two hours of fasting before and after
the dose is considered acceptable.
However, when it is recommended that the study drug be
given with food (as would be in routine clinical practice),
or where the dosage from is a modified release product, fed
state studies need to be carried out in addition to the fasting
state studies.
Fed state studies are also required the consumption of a
high fat breakfast before dosing.
Such a breakfast must be designed to provide 950 to 1000
Kcals.
At least 50% of these calories must come from fat, 15 to
20% from proteins and the rest from carbohydrates.
The vast ethic and cultural variations of the Indian sub
continent preclude the recommendation of any single
standard high fat breakfast.

22. Characteristics to Be Investigated During Bioequivalence Studies
In most cases evaluation of bioavailability and bioequivalence will be based upon the
measured concentrations of the active drug substances in the biological matrix.
In some situations, the measurements of an active or inactive metabolite may be
necessary.
These situations include:
 Where the concentrations of the drugs may be too low to accurately measure in the
biological matrix.
 Limitations of the analytical method .
 Unstable drugs.

23. b) The Crossover Design
A crossover design is a modified, randomized block design in which
each block receives more than one formulation of a drug at different time
periods. A block may be a subject or a group of subjects.
Subjects in each block receive a different sequence of formulations.
There are several situations, where it is essential to go for the
crossover designs like: (i) the formulations do not have a serious damaging
effect on the subjects
(ii) subjects require special training over a long period of time
(iii) objective of the experiment is to find out the effect of different subjects
(iv) homogeneous subjects are scarce
(v) budget constraint

24. Biopharmaceutics classification system
 It is a scientific framework for classifying drug substances based on
their aqueous solubility and intestinal permeability.
 It is a drug-development tool that allows estimation of the
contributions of three major factors, dissolution, solubility and
intestinal permeability that affect oral drug absorption from IR
solid oral dosage forms.
 It was first introduced into regulatory decision-making process in
the guidance document on immediate release solid oral dosage
forms: Scale-up and postapproval changes.
 The drugs are divided into high/low-solubility and permeability
classes. Currently, BCS guidelines are provided by USFDA, WHO
and EMEA.

25. Three necessary steps for a drug to be absorbed are:
 Release of drug from dosage forms.
 Maintenance of dissolved state through gastro-intestinal tract.
 Permeation through G.I membrane into hepatic circulation.
Concept Behind BCS
 The in- vivo performance of orally administered drug depends upon their solubility and
tissue permeability characteristics
 The release rate or solubility of the drug substance will not be a partameter if the
absorption of the drug is permeation rate limited and in such cases the in-
vitrodissolution study can be used to demonstrate the bioavailability or bioequivalence
of the drug product through in vitro- in vivo correlation (IVIVC)

26. Classification
According to BCS, drug substances or APIs are divided into high/
low solubility and permeability classes as follow:
Class I : High Solubility - High Permeability
Class II : Low Solubility - High Permeability
Class III : High Solubility - Low Permeability
Class IV : Low Solubility - Low Permeability

27. Class I drugs exhibit a high absorption number and a high
dissolution number.
The rate-limiting step is drug dissolution and
if dissolution is very rapid then gastric emptying rate becomes the
rate-determining step.
Class II drugs have a high absorption number
but a low dissolution number.
In vivo drug dissolution is then a
rate-limiting step for absorption except at a very high dose number.
The absorption for Class II drugs is usually slower than Class I and
occurs over a longer period of time.
In the case of Class III drugs,
permeability is a rate-limiting step for drug absorption.
These drugs exhibit a high variation in the rate and extent of drug absorption.
Because the dissolution is rapid, the variation is attributable to
alteration of physiology and membrane permeability rather than
the dosage form factors. Generally,
Class IV drugs exhibit problems
for effective oral administration. Examples of drugs for different
classes are given in Table.

29. Purpose of the BCS guidance
 Expands the regulatory application of the BCS and recommends method for classifying
drugs
 Explains when a waiver for in vivo bioavailability and bioequivalence studies may be
requested based on the approach of BCS
Objective of BCS
 To improve the efficiency of the drug development and review process by
recommending , a strategy for identifying expendable clinical bioequivalence test.
 To recommended a class of immediate release solid oral dosage forms for which
bioequivalence may be assessed based on in-vitro dissolution tests.
 To recommend methods for classification according to dosage form dissolution along
with the solubility- permeabilty characteristics of the drug products.

30. Parameters of BCS
Drugs are classified in BCS on the basis of following parameters-
 Solubility
 Permeability
 Dissolution
Solubility class Boundaries –
It is based on the highest dose strength of an immediate release product.
A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of
aqueous media over the pH range of 1 to 7.5
Permeability class boundaries –
It is based indirectly on the extend of absorption of a drug substance in humans and directly on the
measurement of rates of mass transfer across human intestinal membrane
Dissolution class boundaries –
An immediate release product is considered rapidly dissolving when no less than 85% of the labeled
amount of the drug substances dissolve with in 15 minutes using USP dissolution Apparatus – I at
100 RPM or apparatus -II at 50 RPM in a volume of 900 ml or less in the following media: 0.1 N
HCL or simulated gastric fluid or pH 4.5 buffer and pH 6.8 buffer or simulated intestinal fluid.