This document provides an introduction to bioequivalence studies, including definitions of key terms, the need for and importance of bioequivalence studies, criteria for establishing a bioequivalence requirement, types of bioequivalence studies, design of bioequivalence studies, evaluation of bioequivalence study results, and clinical significance. It discusses in vivo and in vitro bioequivalence study types and designs, including factors such as single dose, multiple dose, fasting, food effect, and crossover designs. Statistical evaluation methods including ANOVA, confidence intervals, and bioequivalence limits of 80-125% are also summarized.
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
Methods For Assesment Of Bioavailability Anindya Jana
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. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Bioavailability & Bioequivalence Studies
https://youtube.com/vishalshelke99
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Sub :- Research Methodology
M.Phrmacy Semister 1
Savitribai Phule Pune University
Bioavailability:
Bioavailability is defined as a measure, of the rate and amount of drug, which reaches the systemic circulation unchanged following the administration of a dosage form.
Absolute bioavailability:
When systemic availability of a drug administered orally
is determined in comparison to its I.V. administration, denoted by F.
Relative bioavailability:
When systemic availability of a drug after oral administration is
Compared with that of oral standard of the same drug
( Solution or suspension ) and denoted by Fr.
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGNN Anusha
BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
1. Measurement of Bioavailability:
Direct and indirect methods may be used to assess drug bioavailability. The in-vivo bioavailability of a drug product is demonstrated by the rate and extent of drug absorption, as determined by comparison of measured parameters, e.g., concentration of the active drug ingredient in the blood, cumulative urinary excretion rates, or pharmacological effects.
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
The design of the bioavailability study depends on the objectives of the study, the ability to analyze the drug (and metabolites) in biological fluids, the pharmacodynamics of the drug substance, the route of drug administration, and the nature of the drug product.
Pharmacokinetic and/or pharmacodynamic parameters as well as clinical observations and in-vitro studies may be used to determine drug bioavailability from a drug product.
1.1. Pharmacokinetic methods:
These are very widely used and based upon the assumption that the pharmacokinetic profile reflects the therapeutic effectiveness of a drug. Thus these are indirect methods. The two major pharmacokinetic methods are:
The major pharmacokinetic methods are:
Plasma / blood level time profile.
o Time for peak plasma (blood) concentration (t max)
o Peak plasma drug concentration (Cmax)
o Area under the plasma drug concentration–time curve (AUC)
Urinary excretion studies.
o Cumulative amount of drug excreted in the urine (Du)
o Rate of drug excretion in the urine (dDu/dt)
o Time for maximum urinary excretion (t)
C. Other biological fluids
1.2. Pharmacodynamic methods:
IT involves direct measurement of drug effect on a (patho) physiological process as a function of time. Disadvantages of it may be high variability, difficult to measure, limited choices, less reliable, more subjective, drug response influenced by several physiological & environmental factors.
They involve determination of bioavailability from:
Acute pharmacological response.
Therapeutic response.
1.3. In-vitro dissolution studies
Closed compartment apparatus
Open compartment apparatus
Dialysis systems.
1.4. Clinical observations
Well-controlled clinical trials
Methods For Assesment Of Bioavailability Anindya Jana
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. For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action.
Bioavailability studies are important in the Primary stages of development of a suitable dosage form for a new drug entity, determination of influence of excipients, patient related factors & possible interaction with other drugs on the efficiency of absorption, development of new formulations of the existing drugs, control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption
United State Pharmacopoeia (USP)The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage form.
Food and Drug Administration (FDA) definitionIVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response. Generally, the in vitro property is the rate or extent of drug dissolution or release while the in vivo response is the plasma drug concentration or amount of drug absorbed.
Bioavailability & Bioequivalence Studies
https://youtube.com/vishalshelke99
https://instagram.com/vishal_stagram
Sub :- Research Methodology
M.Phrmacy Semister 1
Savitribai Phule Pune University
Bioavailability:
Bioavailability is defined as a measure, of the rate and amount of drug, which reaches the systemic circulation unchanged following the administration of a dosage form.
Absolute bioavailability:
When systemic availability of a drug administered orally
is determined in comparison to its I.V. administration, denoted by F.
Relative bioavailability:
When systemic availability of a drug after oral administration is
Compared with that of oral standard of the same drug
( Solution or suspension ) and denoted by Fr.
In this presentation I have mentioned whatever the possible relevant content/guidelines require for biowaiver application.
Citation Is done at the end of slide.
Content is up to date & true to my belief.
Thanks & Best Regards.
Anurag Pandey
B.Pharm (FACULTY OF PHARMACY, INVERTIS UNIVERSITY)
M.Pharm (INSTITUTE OF PHARMACY, NIRMA UNIVERSITY)
Email :- anurag.dmk05@gmail.com
PHARMACOKINETIC MODELS
Drug movement within the body is a complex process. The major objective is therefore to develop a generalized and simple approach to describe, analyse and interpret the data obtained during in vivo drug disposition studies.
The two major approaches in the quantitative study of various kinetic processes of drug disposition in the body are
Model approach, and
Model-independent approach (also called as non-compartmental analysis).
BIOPHARMACEUTIC CONSIDERATIONS IN DRUG PRODUCT DESIGNN Anusha
BIOPHARMACEUTICS studies the in vitro impact of physicochemical properties of drugs and drug products on delivery to body under normal or pathologic conditions.
Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in vivo.
The aim of biopharmaceutics is to adjust the delivery of drug from drug products in such a manner as to provide: optimal therapeutic activity and safety for the patient.
Bioequivalence studies for various pharmaceutical drug formulations manufactured and released into the market is outlined in this presentation. The various studies used to establish bioequivalency with the original formulation is also mentioned.
It refers to the drug substance in two or more identical dosage forms , reaches systemic circulation at he same rate and to the same relative extent .
Their plasma concentration –time profile will be identical without significant statistical differences.
It refers to the drug substance in two or more identical dosage forms , reaches systemic circulation at he same rate and to the same relative extent .
Their plasma concentration –time profile will be identical without significant statistical differences.
1. PREPARED BY: PARTH
M.PHARM SEM-I (Q . A)
GUIDED BY : Ms.TANVI PANDYA
DEPARTMENT OF Q. A
A.P.M.C.COLLEGE OF PHARMACY
HIMMATNAGAR
2. CONTENT
Introduction
Need for Bioequivalence studies
Importance of Bioequivalence studies
Criteria for Establishing a bioequivalence requirement
Types of Bioequivalence studies
Design of Bioequivalence studies
Evaluation of Bioequivalence study
Clinical significance
References
3. INTRODUCTION
DEFINITIONS:
Bioavailability:
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.
Equivalence:
It is a relative term that compares drug products with respect to a
specific characteristic or function or to a defined set of standards.
There are several types of equivalences:
• Chemical equivalence: It indicates that two or more drug
products contain the same labeled chemical substance as an
active ingredient in the same amount.
4. Pharmaceutical equivalence: This term implies that two or more
drug products are identical in strength, quality, purity, content
uniformity and disintegration and dissolution characteristics. They
may, however differ in containing different excipients.
Bioequivalence: denotes that the drug substance in two or more
identical dosage forms, reaches the systemic circulation at the same
relative rate and to the same relative extent i.e. their plasma
concentration-time profiles will be identical without significant
statistical differences. When statistically significant differences are
observed in the bioavailability of two or more drug products, bio-in
equivalence is indicated.
• Therapeutic Equivalence: This term indicates that two or more
drug products that contain the same therapeutically active
ingredient elicit identical pharmacological effects and can control
the disease to the same extent.
5. NEED FOR BIOEQUIVALENCE STUDIES
New product is intended to be a substitute for an approved
medicinal product as a pharmaceutical equivalent or alternative
To ensure clinical performance of such drug products
Bioequivalence studies are conducted if there is:
A risk of bio-in equivalence and/or
A risk of pharmacotherapeutics failure or diminished clinical
safety
In vivo bioavailability / bioequivalence studies and in vitro
dissolution testing recommended to applicants intending to
submit Investigational new drug application (INDs)New drug
applications (NDAs)Abbreviated new drug applications
(ANDAs) for conventional and extended release dosage forms
administered orally.
6. In conditions where a suitable method for determining active
drug is not available, an indirect indication of bioavailability
and bioequivalence by comparing the pharmacodynamic
responses of the formulations may be possible
7. IMPORTANCE OF BIOEQUIVALANCE STUDIES
To evaluate the absolute bioavailability of dosage form compared
with reference dosage forms.
Dose proportionality study to determine if bioavailability
parameters are linear over proposed dosage range.
Intra/inter subject variability
Intervention study to examine effect of e.g. Food and concomitant
medication.
Dosage form proportionality study to determine if equipotent drug
treatments administered at different dose strength of the market
form produce equivalent drug bioavailability.
Bioequivalence study needed as a result of changes in the
formulation or manufacturing processes.
8. CRITERIA FOR ESTABLISHING A BIOEQUIVALENCE
REQUIREMENT
Evidence from well-controlled clinical trials, or controlled
observations in patients and bioequivalence studies :
Various drug products do not give comparable therapeutic
effects are not bioequivalent drug products.
Narrow therapeutic ratio and minimum effective concentration
in the blood.
Serious adverse effects
Physicochemical:
Low solubility in water.
Dissolution rate slow
Particle size and surface area of the active drug ingredient
9. Structural forms dissolves poorly.
High ratio of excipients.
Hydrophilic or hydrophobic excipients and lubricants
• Pharmacokinetic:
GI tract or localized site.
Degree of absorption poor
10. TYPES OF BIOEQUIVALANCE STUDIES
In vivo:
1. Oral immediate-release products with systemic action
Indicated for serious conditions requiring assured response.
Narrow therapeutic margin.
Absorption <70%
Unfavorable physiochemical properties.
Bioavailability problems.
2. Non-oral immediate-release products.
3. Modified-release products with systemic action.
11. In vitro:
Dissolution study can be used in lieu of in vivo bioequivalence
under certain circumstance, called as biowaivers.
1. The drug product differs only in strength of the active substance
it contains, provided all of the conditions hold-
Pharmacokinetics linear.
Qualitative composition same.
Ratio between active substance and the excipients are same.
Same manufacturer and same production site.
Bioavailability or bioequivalence study performed with the
original product.
2. Slightly reformulated or manufacturing method slightly modified
by the original manufacturer.
12. 3. Meets all of the following requirements-
Solution or solublised form
Active ingredient in the same concentration
No excipients
Topical administration
Oral administration
By inhalation as a gas or vapour.
13. DESIGN OF BIOEQUIVALENCE STUDIES
DESIGN:
The design and evaluation of well-controlled bioequivalence
studies require cooperative input from
pharmacokineticists, statisticians, clinicians, bioanalytical
chemists, and others.
The basic design for a bioequivalence study is determined by:
The scientific questions to be answered,
The nature of the reference material and the dosage form to be
tested,
The availability of analytical methods, and
Benefit–risk and ethical considerations with regard to testing
in humans. For some generic drugs, the FDA offers general
guidelines for conducting these studies.
14. Bioequivalence study protocol
1. Title c.Dosage regimen
a. Principal investigator d. Sample collection schedule
b. Project number & date e. Housing
2. Study objective f. Fasting/meals schedule.
3. Study design g. Analytical methods
a. Design 4. Subject selection
- Medical history
b.Drug product
- Physical examination
- Test products
- Laboratory tests.
- Reference product
c. Inclusion/exclusion criteria
15. 5. Clinical procedures
a. Dosage & drug e. Adverse reactions &
administration emergency procedures.
b. Biological sampling 7. Facilities
schedule 8. Data analysis
c. Activity of subjects 9.Analytical validation
6. Ethical considerations procedure
a. Basic principles a. Drug accountability
b. Institutional review board b. Statistical treatment of
c. Informed consent data
d. Indications for subject 10. Appendix
withdrawal
16. • Detailed protocol
• Same dose strength, similar dosage forms and same route of
administration.
• No unnecessary human research
• Normal, healthy male volunteers given informed consent.
• Fasted 10 to 12 hours prior to drug administration and 2 to 4 hour
after dosing.
Reference standard
Same route
Fully approved
Innovator’s or original manufacturer
Brand name product
In vivo: 5% of the reference product
In vitro:Both test and reference
17. Study designs:
Fasting study
• Single dose, two-period, two-treatment, two sequence, open
label, randomized cross over designs.
• Fasted, adult, healthy subjects.
• All immediate release and modified release oral dosage forms
• Both male and female subjects
• Overnight fast and 4 hour after dosing
Food intervention study
• Co-administration of food with an oral drug product may affect
the bioavailability of the drug.
18. Multiple dose
• Multiple dose, steady state, randomized, two-treatment, two-
way, crossover study.
• Adult and healthy subject
• Three consecutive trough concentration on three consecutive days
Types of test designs
1.Completely randomized designs
All treatments( factor levels) are randomly allocated among all
Experimental subjects.
Method of randomization : label all subjects with the same number
digits. Randomly select non-repeating numbers.
Advantages:-
Easy to construct.
19. Any number of treatments & subjects.
Easy & simple to analyses.
Disadvantages:-
Best suited for relatively few treatments.
All subjects must be as homogenous
2. Randomized block designs
Subjects are sorted into homogenous groups called blocks.
Method of randomization: Subjects having similar background
characteristics are formed as blocks.
20. Then treatments are randomized within each block, just like the
simple randomization.
Advantages:-
Effective & systemic way of grouping.
Any number of treatments or replications.
Different treatments need not have equal sample size.
Statistical analysis simple & easy to construct.
Spoiled results, the design is easy to construct.
Disadvantages:-
More complex analysis
Degrees of freedom of experimental error are not as large as
with a completely randomised design.
21. Repeated measures, cross-over & carry-over designs:-
• Same subject serves as a block.
• Repeated measures on each subject we get the design name
“repeated measures design”
• The administration of two or more treatments one after the other in
a specified or random order to the same group of patients is called
a crossover design or change-over design
• Carry over effects
• Wash out period
Advantages:
Good precision for comparing treatments
Economic on subjects
22. Disadvantages:
Order-effect.
Carry over effect.
Latin Square designs:
• Each Subject receives each treatment during the course of the
experiment.
• A Latin square design is a two factor design with one
observation in each cell.
• Rows represent subjects & columns represent treatments.
• Standard: the first row & the first column consist r letters in
alphabetical order.
23. Latin-Square Crossover Design for a Bioequivalence Study of Three
Drug Products in Six Human Volunteers
Drug Product
Subject Study Washout Study Washout Study
Period 1 period 1 Period 2 period 2 Period 3
1 A B C
2 B C A
3 C A B
4 A C B
5 C B A
6 B A C
24. Advantages:
Minimizes inter-subject variability, Intra-subject variability &
time effect.
Formulation variables.
Disadvantages:-
Degrees of freedom for experiments error larger than
necessary.
More complex.
Wash out period very long
25. Evaluation of bioequivalence studies
Analytical method
• Accuracy, precision and specificity.
• More than one analytical method not be valid.
• Data presented in both tabulated and graphical form
• Plasma drug concentration versus time curve for each drug
product and each subject.
Pharmacokinetic evaluation of the data
• Single dose study:AUC0-t ,AUC0-∞,Tmax and Tmax.
• Multiple dose studies:AUC0-t,Tmax,Cmax,Cmin and percent
fluctuation[100*(Cmax-Cmin)/Cmin].
26. Statistical evaluation of the data
• No statistical difference between the bioavailability of the test
product & the reference product.
• Bell- shaped curve
• Log values resembles more closely a normal distribution
Analysis of variance(ANOVA)
• No significance difference.
• AUC0-24,AUC0-∞, Tmax & Cmax
• Evaluate variability in subjects , treatment groups, study
period, formulation & other variables.
• Variability in the data is large then two drug products are
bioequivalent.
• Statistically significant, If p≤0.05
• P- level of Statistical significance.
27. • If p> 0.05 the difference between the two drug products are not
statistically significant.
• To detect small differences between the test products, a power
test is performed.
• Sample size, variability of the data & desired level of
significance.
• Power is set at 0.80 with an α=0.2 & a level of significance of
0.05.
28. Two one-sided tests procedure
• Confidence interval approach.
• Greater 20%.
• 90% confidence limits.
• Student’s t-distribution of the data.
• within 20%.
• Lower 90% confidence interval for the ratio of means cannot
be less than 0.80 & the upper 90% confidence interval for the
ratio of the means cannot be greater than 1.20.
• Log transformed data , 90% confidence interval is set at 80 to
125%.
29. • Confidence limits termed the bioequivalence interval.
• No-statistical differences between the mean AUC & Cmax
parameters.
• 90% confidence intervals for AUC & Cmax values of the test
drug product should not be less than 0.80(80%) nor greater
than 1.25(125%) of the reference product based on log-
transformed data.
30. CLINICAL SIGNIFICANCE
Clinical interpretation is important in evaluating the results of
a bioequivalence study.
Differences of less than 20% in AUC & Cmax between drug
products are unlikely to be clinically significant in patients.
A small, statistically significant difference if the study well
controlled & the number of subjects is sufficiently large.
Above MEC & do not reach the MTC.
Elderly or patients.
Normal healthy volunteers.
Minimize product to product variability by different
manufactures & lot to lot variability with a single manufacture.
31. REFERENCES
Leon Shargel; Andrew B.C Yu, Applied Bio pharmaceutics and
pharmacokinetics, Fourth edition,pp 256-271.
D.M.Brahmankar, Sunil b. jaiswal, Biopharmaceutics and
Pharmacokinetics, A Treatise, second edition, vallabh
prakashan,pp336-344.