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Bioavailability and Bioequivalence

The document outlines the concepts of bioavailability and bioequivalence in pharmaceuticals, detailing their definitions, objectives, and significance in ensuring drug efficacy and safety. It discusses measurement methods, including pharmacokinetic and pharmacodynamic approaches, as well as in-vitro drug dissolution models and their correlations with in-vivo responses. Additionally, it emphasizes the importance of bioequivalence studies in comparing generic and innovative drug formulations to ensure therapeutic equivalence.

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0% found this document useful (0 votes)
22 views33 pages

Bioavailability and Bioequivalence

The document outlines the concepts of bioavailability and bioequivalence in pharmaceuticals, detailing their definitions, objectives, and significance in ensuring drug efficacy and safety. It discusses measurement methods, including pharmacokinetic and pharmacodynamic approaches, as well as in-vitro drug dissolution models and their correlations with in-vivo responses. Additionally, it emphasizes the importance of bioequivalence studies in comparing generic and innovative drug formulations to ensure therapeutic equivalence.

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zaidkhan0000056
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PHARMACEUTICS I [Theory]

B. Pharma. - VIst sem


Bioavailability and Bioequivalence
BY
Dr. Prashant Kesharwani
Syllabus

Bioavailability and Bioequivalence: Definition and Objectives of


bioavailability, absolute and relative bioavailability, measurement
of bioavailability, in-vitro drug dissolution models, in-vitro-in-vivo
correlations, bioequivalence studies, methods to enhance the
dissolution rates and bioavailability of poorly soluble drugs.
Introduction
✓ Essential to ensure uniformity in standards of quality, efficacy & safety of Pharmaceutical
products
✓ Reasonable assurance is to be provided that various products containing same active
ingredient, marketed by different licensees are clinically equivalent & interchangeable
✓ Release of an active substance should be known & reproducible
✓ Both Bioavailability & Bioequivalence focus on release of drug substance from its dosage
form & subsequent absorption in circulation
✓ BA/BE focus on the release of the drug from the dosage form and absorption in to the
systemic circulation.
✓ BE for the comparison of the two drug, several test method are given to determine the
equivalence.
Objectives of bioavailability–
1. Primary stages of development of a suitable dosage form for a new drug entity to obtain
evidence of its therapeutic utility.
2. Determination of influence of
- excipients,
- patient related factors,
- possible interaction with other drugs on the efficiency of absorption.
3. Development of new formulations of the existing drugs.
4. Control of quality of a drug product during the early stages of marketing in order to
determine the influence of processing factors, storage and stability on drug absorption.
5. Comparison of availability of a drug substance from different dosage forms or form the
same dosage form produced by different manufacturers.
Why do we care about
BIOAVAILABILITY?
• The “true dose” is not the drug swallowed; BUT is the drug available to exert its effect.
• Dissolution
• Absorption
• Survive metabolism
• Drug may be extensively metabolized during absorption process (first-pass, gut wall, liver).
Important component of overall variability
i.e. Variable bioavailability may produce variable exposure.
• To study various objective of bioavailability and to known significance of bioavailability.
• To study various measurement parameters used in measurement of bioavailability.
BIOAVAILABILITY

BIOAVAILABILITY: According to 2003 FDA guidance,


‘Bioavailabilty’ is defined as 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. For
the products that are not intended to be absorbed into blood stream, bioavailability may
be assessed by measurement intended to reflect the rate and extent to which the active
ingredient or active ingredient or active moiety becomes available at the sit of action
Bioavailable fraction (F), refers to the fraction of administered dose that enters the
systemic circulation

𝐵𝑖𝑜𝑎𝑣𝑎𝑖𝑙𝑎𝑏𝑙𝑒 𝑑𝑜𝑠𝑒
F=
𝐴𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑 𝑑𝑜𝑠𝑒
Types of bioavailability
There are two types bioavailability
1. Absolute Bioavailability
2. Relative Bioavailability
1. Absolute Bioavailability
i. Compares the bioavailability of the active drug in systemic circulation following non-
intravenous administration with the same drug following intravenous administration
ii. For drugs administered intravenously, bioavailability is 100%
iii. Determination of the best administration route

𝐴𝑈𝐶 𝑒𝑥𝑡𝑟𝑎𝑣𝑎𝑠𝑐𝑢𝑙𝑎𝑟 𝑋 𝐷𝑂𝑆𝐸𝑖𝑣


Fab=
𝐴𝑈𝐶 𝑖𝑣 𝑋 𝐷𝑂𝑆𝐸𝑒𝑥𝑡𝑟𝑎𝑣𝑎𝑠𝑐𝑢𝑙𝑎𝑟
AUC = Area under the curve
2. Relative Bioavailability (Frel)
i. Compares the bioavailability of a formulation (A) of a certain drug when compared
with another formulation (B) of the same drug, usually an established standard
𝐴𝑈𝐶 𝑡𝑒𝑠𝑡 𝑋 𝐷𝑂𝑆𝐸(𝑅𝑒𝑓)
Frel =
𝐴𝑈𝐶 𝑅𝑒𝑓 𝑋 𝐷𝑂𝑆𝐸 (𝑡𝑒𝑠𝑡)

AUC = Area under the curve


Measurement of bioavailability
There are two types of methods for the measurement of bioavailability
A. Pharmacokinetic
(Indirect )
i. Plasma level time studies
ii. Urinary excretion studies
B. Pharmacodynamic
(Direct )
i. Acute pharmacological response
ii. Therapeutic response
Measurement of bioavailability
A. Pharmacokinetic (Indirect ) method
i. Based on assumption that the pharmacokinetic profile reflects the therapeutic
effectiveness of drug.
ii. These are indirect method
B. Pharmacodynamic (Direct ) method
i. Involves direct measurement of drug effect on a (patho) physiological process as a
function of time.
ii. It is direct measurement.
A. Pharmacokinetic method
1. Plasma level-time studies
➢ The method is based on the assumption of 2 dosage forms that exhibit superimposable
plasma level time profiles in a group of subject should result in identical therapeutic
activity.
➢ With single does study, the method requires collection of serial blood samples for a period
of 2 to 3 biological half lives after drug administration, their analysis for drug concentration
and making a plot of concentration versus corresponding time of sample collection to
obtain the plasma level – time profile
➢ With i.v. Does, sampling should start within 5 minutes of drug administration and
subsequent samples taken at 15 minute intervals.
A. Pharmacokinetic method
1. Plasma level-time studies
➢ The three parameters of plasma level time studies which are considered important for
determining bioavailability are:
1. AUC: The AUC is proportional to the total amount of drug reaching the systemic
circulation, and thus characterizes the extent of absorption.
2. Cmax: Gives indication whether drug is sufficiently absorbed systemically to provide a
therapeutic response. It is a function of both the rate and extent of absorption. Cmax will
increase with an increase in the dose, as well as with an increase in the absorption rate.
3. Tmax: The Tmax reflects the rate of drug absorption, and decreases as the absorption rate
increases.
A. Pharmacokinetic method
2. Urinary Excretion studies
• These studies are based on the premise that urinary excretion of the unchanged drug is
directly proportional to the plasma concentration of total drug.
• As a rule of thumb, determination of bioavailability using urinary excretion data should be
conducted only if at least 20% of administered dose is excreted unchanged in the urine.
The study is particularly useful for
i. Drugs that extensively excreted unchanged in the urine.
For example: thiazide diuretics, sulfonamides.
ii. Drug that have urine as the site of action.
For example: Urinary antiseptics : nitrofurantoin, Hexamine.
A. Pharmacokinetic method
2. Urinary Excretion studies
The three major parameters examined in urinary excretion data are as follow:
1. (dXu/dt)max : It gives the rate of appearance of drug in the urine is proportional to its
concentration in systemic circulation. Its value increases as the rate of and/or extent of
absorption increases
2. (tu)max : It is analogous to the plasma level data, its value decreases as the absorption
rate increases.
3. Xu : It is related to the AUC of plasma level data and increases as the extent of absorption
increases.
B. Pharmacodynamic methods
1) Acute Pharmacological Response :
Used when pharmacokinetic methods are difficult, inaccurate & non reproducible an acute
pharmacological effect such as
i. Change in ECG/EEG readings
ii. Pupil diameter.
Disadvantages :
i. More variable and accurate correlation between measured response and available from
the formulation is difficult
ii. Active metabolite interferes with the result.
B. Pharmacodynamic methods
2 ) Therapeutic Response :
Measurement of clinical response to a drug formulation given to patients suffering from
disease for which it is intended to be used.
Disadvantages :
i. Improper quantification of observed response.
ii. Bioequivalence studies are usually conducted using a crossover design.
In-vitro drug dissolution models
✓ Dissolution and drug release tests are in-vitro tests that measure the rate and extent of
dissolution or release of the drug substance from a drug product, usually aq. medium
under specified conditions.
✓ It is an important QC procedure for the drug product and linked to product performance
in-vivo.
NEED FOR DISSOLUTION TESTING:
• Evaluation of bioavailability
• Batch to batch drug release uniformity
• Development of more efficacious and therapeutically optical dosage forms
• Ensures quality and stability of the product
• Product development, quality control, research and application
In-vitro dissolution models
For non-sink condition
1) Natural convection non sink methods:
a) Klein solvmeter method
b) Nelson hanging pellet method
c) Levy static disk method
2) Forced convection non sink methods:
a) Tumbling method
b) Levy or Beaker method
c) Rotating disk method
d) Particle size method
e) USP Rotating basket apparatus
f) USP Paddle apparatus
For sink condition
3) Forced convection sink devices:
a) Wurster pollis adsorption method
b) Partition method
c) Dialysis method s
d) Rotating disk apparatus
4) Continous flow/flow through methods:
a) Pernarowski method
b) Langenbucher method
c) Baun and Walker
d) Tingstad and Reigelman
e) Modified column apparatus
In-vitro-in-vivo correlations (IVIVC)

Definition
FDA: A predictive mathematical model describing the relationship between an in vitro
property of dosage form (usually the rate or extent of drug dissolution or release) and a
relevant in vivo response, e.g., plasma drug concentration or amount of drug

USP: The establishment of a relationship between a biological property or a parameter


derived from a biological property (Cmax, AUC) produced by a dosage form, and a
physicochemical characteristic (in vitro release) of the same dosage form.
In-vitro-in-vivo correlations

❖ Systemic absorption of drugs is a prerequisite for eliciting their therapeutic activity,


whenever given non instantaneously
❖ As per federal guidelines, all the oral dosage forms have to be evaluated for their in
vivo bioavailability
❖ Thus, generic manufacturers must provide detailed bioequivalence evidence
showing head-to-head comparative performance of their product against reference
❖ Conduct of such biostudies is a Herculean task involving myriad technical,
economical and ethical issues
❖ Also, development and optimization of a formulation is an time consuming and
costly process
In-vitro-in-vivo correlations

❖ This may require alteration in formulation composition manufacturing process,


equipment and batch size
❖ These type of changes call for the need of BA studies to prove that new formulation is
bioequivalent with the old one
❖ Implementation of these requirements :
i. Halt the marketing of new formulation
ii. Increase the cost of optimization process
iii. Demand for strict regulatory guidelines to be followed
❖ Thus, it would be very convenient if inexpensive in vitro experiments could be
substituted for in vivo bioavailability tests.
In-vitro-in-vivo correlations
❖ For in vitro test to be useful in this context, it must predict in vivo behavior to such an
extent that in vivo bioavailability test becomes redundant.
❖ In vitro dissolution is one such test that can predict the in vivo performance of a drug.
❖ For in vitro dissolution to act as surrogate for bioavailability studies an accurately
validated correlation needs to be established between in vitro and in vivo performance
of drug.
❖ Thus, by establishing IVIVC , in vitro dissolution can act as surrogate for bioequivalence
studies
❖ This would circumnavigate the hiccups caused by the biostudies by seeking for requisite
biowaivers.
In-vitro-in-vivo correlations

❖ The concept of IVIVC has been extensively discussed for modified release dosage forms.
❖ This is because the dissolution behavior of of the drug from ER or MR product is the rate
limiting factor for absorption in GIT
❖ This is why IVIVC are expected more generally for ER formulations than with IR products
especially when the latter releases the drug rapidly (>80 % in < 20 minutes) But, it does
not mean that IVIVC cannot be applied for IR products
❖ In recent times, IVIVC for parenterals, transdermals, pulmonary formulations etc. are
also coming
Bioequivalence studies
Bioequivalence (BE): the absence of a significant difference in the rate and extent to which
the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical
alternatives becomes available at the site of drug action when administered at the same
molar dose under similar conditions in an appropriately designed study
Two products are bioequivalent if
• They are pharmaceutically equivalent
• Bioavailability's (both rate and extent) after administration in the same molar dose are
similar to such a degree that their effects can be expected to be essentially the same
Pharmaceutical Equivalents
• Contain the same amount of the same active substance in the same dosage form meet
the same or comparable standards intended to be administered by the same route
• Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalence
Bioequivalence studies
Bioequivalence studies
Therapeutic equivalence
Two products are therapeutically equivalent if
• Pharmaceutically equivalent
• Their effects, with respect to both efficacy and safety, will be essentially
the same as derived from appropriate studies
i. Bioequivalence studies
ii. Pharmacodynamic studies
iii. Clinical studies
iv. In vitro studies
Bioequivalence studies
Need of bioequivalence studies
❖No clinical studies have been performed in patients with the Generic Product to support
its Efficacy and Safety
❖With data to support similar in vivo performance (= Bioequivalence) Efficacy and Safety
data can be extrapolated from the Innovator Product to the Generic Product.
Ultimate: Bioequivalence studies impact of changes to the dosage form process after pivotal
studies commence to ensure product on the market is comparable to that upon which the
efficacy is based
Bioequivalence studies
Goals of BE
Ultimate: Bioequivalence studies impact of changes to the dosage form process after pivotal
studies commence to ensure product on the market is comparable to that upon which the
efficacy is based
• Establish that a new formulation has therapeutic equivalence in the rate and extent of
absorption to the reference drug product
• Important for linking the commercial drug product to clinical trial material at time of NDA
• Important for post-approval changes in the marketed drug formulation
NDA vs. ANDA Review Process

Original Drug Generic Drug


NDA Requirements (Innovative product) ANDA Requirements
Chemistry Chemistry
Manufacturing Manufacturing
Controls Controls
Labeling Labeling
Testing Testing
Animal Studies -
Clinical Studies Bioequivalence Study (In
(Bioavailability/Bioequivalence) Vivo, In vitro)
Methods to enhance the dissolution rates
Dissolution “ Dissolution is the process by which a solid phase goes into solution”

Dissolution Rate “Dissolution rate may be defined as the amount of drug substance that goes in to
solution per unit time under standardized conditions of liquid-solid interface, temperature & solvent
composition.” Dissolution rate is given by Noyes-Whitney equation-
Under non sink condition dc/dt = KS (Cs-C) dc/dt =DS/h (Cs-C)
Where ,
dc/dt = rate of drug dissolution, K= dissolution rate constant, S=surface area of the particle, (Cs-
C)=concentration gradient, D= diffusion coefficient of drug in solution, h= thickness of diffusion layer.
Process of dissolution : The process of dissolution involves breaking of inter-ionic or intermolecular bonds in
the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, and
the interaction between the solvent and solute molecule or ion.
Methods to enhance the dissolution rates

Method to increase dissolution rate


1. Increasing the effective surface area of the drug
2. Particle size reduction
3. Incorporation of Surface Active Agents
4. Solid Dispersions
5. Polymorphism
6. The use of Metastable Polymorphs
7. Molecular Encapsulation
8. Prodrug Approach
9. Salt form of the drug
10. Nanosuspension
11. Ternary systems

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