bioequivalence : bioequivalence Presented by : SANKET B REKHAWAR
Guided by : M.S. PARA
S.V.E.T’S COLLEGE OF PHARMACY
HUMNABAD Introduction : Introduction Bioequivalence is a comparison of bioavailability of two or more product i.e. Formulation containing the same active ingredient are said to be bio-equivalent if their rate & extent of absorption is same.
One of the best way to compare two product is by clinical studies. But performing clinical studies is extremely cumbersome & expensive. Hence Bio-equivalence studies are generally used to compare two products so as to compare their biological equivalence.
Bioequivalence is receiving increasing attention because of increased availability & importance of generic drugs in today's p’ceutical market. Slide 3: However bioequivalence is not straight forward for all the drugs . Many drugs shows bioinequivalence.
In 1973 ad hoc committee on drug product selection of American Pharmaceutical Association published a list of drug that show bioinequivalence.
Based on this list drug has been divided into 3 categories IMPORTANT DEFINITIONS:- : IMPORTANT DEFINITIONS:- Chemical equivalence:-
It indicate that two or more drug products contain the same labeled chemical substance as an active ingredient in same amount.
Pharmaceutical Equivalence:- This term implies that two or more drug products are identical in strength, quality, purity, content uniformity & disintegration & dissolution characteristics. Slide 5: Bioequivalence:-
It is relative term which denotes that drug substances in two or more identical dosage forms, reaches the systemic circulation at the same relative rate and to the same relative extent.
This term indicates that two or more drug product that contains same therapeutically active ingredient, elicit identical pharmacologic effects & can control the disease to the same extent's. Bioequivalence Studies : Bioequivalence Studies Difference in predicted clinical response may be due to difference in pharmacokinetics, pharmacodynamics or bioavailability of drug products .
Bioequivalent drug products that have same systemic drug bioavailability will have same predictable response .
Difference in pharmacodynamics behavior is due to age, drug tolerance, drug interaction etc.
Bioavaliability of drug may be more during empty stomach
When drug is used on daily basis, nature of an individuals diet & lifestyle may affect plasma drug level because variable absorption in the presence of food. Bases for determining bioequivalence : Bases for determining bioequivalence Bioequivalence is established if the in-vivo bioavaliability of test drug product (usually generic product) does not differ significantly in rate & extent of drug absorption, from reference listed drug (brand name product) administered at same dose, under similar experimental conditions. BIOEQUIVALENCE PROBLEMS : BIOEQUIVALENCE PROBLEMS Bioequivalence problem occurs due to following reason-
Active drug ingredient has low solubility in water . (less than 5 mg/ml) .
Dissolution rate is low.
Certain structural forms of active drug ingredient (e.g. polymorphic forms, solvates, complexes & crystal modifications) dissolve poorly, thus altering the absorption.
Drug product that have high ratio of excipients to active ingredients (e.g. greater than 5:1) .
Specific ingredients such as hydrophilic & hydrophobic excipient & lubricant may interfere with absorption .
Active ingredients absorbed in particular segment of GIT.
The degree of absorption of active drug ingredient is poor when administered in pure form.
Rapid metabolism in intestinal wall or in liver during absorption process. BIOEQUIVALENCE STUDY : BIOEQUIVALENCE STUDY Parameters
AUC:- Area under plasma drug concentration time curve. AUC Provides information regarding amount of drug in plasma i.e. extent of release.
C max:- Maximum plasma drug concentration. Partly depends on rate of drug release from the formulation.
T max:- Time required to reach maximum plasma drug concentration
Tmax is also dependent on rate of drug release from the formulations. Pharmacokinetic StudiesKey Measurements : Pharmacokinetic StudiesKey Measurements AUC
Area under the concentration- time curve
A difference of greater than 20% in Cmax or the AUC represents a significant difference between the study and reference compounds
Time to maximum concentration Study Compound
Reference Compound Time Concentration Cmax Tmax AUC 4. Plasma Through fluctuation(%):- : 4. Plasma Through fluctuation(%):- This parameter is generally used in bioequivalence studies of sustained release formulation.
It can be calculated as
%PTF= C max-C min
Where C average is Avg Plasma drug conc. During dosing period. Slide 12: 5. T1/2:- Elimination half life .It provides information regarding elimination of drug from the body.
6. Normalized C max:- C max & T max are known to show significant intersubject variability & hence normalized C max is used in some cases.
It can be calculated as-
Normalized C max= C max
7. Mean residence time(MRT) : It provides an idea about time a drug molecule spend in the body before it get excreted. Study Protocol :- : Study Protocol :- 1.Title
a) Principle investigator( Study director)
b) Project/protocol number & date.
3. Study design
b) Drug products
2. Reference Product
c) Dosage regimen
d) Sample collection schedule
e) Housing/ confinement
f) Fasting/meal schedule
g) Analytical methods
4. Study population
b) Subject selection
1. Medical history
2. Physical examination.
3. Laboratory test. Slide 14: c) Inclusion and exclusion criteria
d) Restriction / prohibitions
5. Clinical procedures
A) Dosage and drug administration
B) Biological sampling schedule
C) Activity of subject
6. Ethical Consideration
A) Basic principles
B) Institutional review board
C) Informed consent
D) Adverse reactions
8. Data analysis
A) Analytical validation procedure
B) Statistical treatment of data
9. Drug accountability
10. Appendix Slide 15: STUDY DESIGN
Bioequivalence study should be designed in such away so as to identify treatment effects that are produced after administration of products.
Two types of design
Generally crossover is used in practice in this design both test and reference product are compared in each subject that is each subject act as his/her own control
Hence inter subject variable such as age ,weight,
metabolism etc. are minimal.
Because of minimal intersubject variability, crossover design is widely used for routine studies.
In this design first subjects are randomly divided in to 2 groups and sequence of drug is randomly assigned. Slide 16: If there are two formulations – test (T) and reference (R) ; in period 1 , group 1 will receive T followed by R.
Time period between administrations of two formulations will be sufficiently long considering adequate ‘wash out period’.
Wash out period is essential to ensure complete elimination of drug before next administration.
10 half lives ensures more than 99% of elimination and hence wash out period should be at least 10 half lives. Slide 17: Period II will start after completion of wash out period now in period II, group 1 will receive ‘R’ followed by ‘T’ .
If drug require washout period of 7 days then sequence of administration of 2 formulation can be shown as
Thus sequence of administration for group I is T-R & group II is R-T .
Two formulation trial is always a 2 period trial,
Thus in period I , 50% subject ( group I) receive T & 50% subject (group II) receive R .
In period II order is reversed Latin square cross over design : Latin square cross over design For biequvalence study in human volenteers
Compares 3 different drug formulations- A,B,& C.
In this design , each subject receives each drug product only once
Adequate time is provided between medications for elimination of drug from the body.
In this design each subject is having his /her own control hence subject to subject variation is reduced. Slide 19: LATIN –SQUARE CROSS OVER DESIGN FOR BIOEQUIVALENCE STUDY OF 3 DRUG PRODUCTS IN 6 HUMAN VOLUNTEERS Slide 20: Subject:-
This study is usually performed with healthy volunteers of both sexes.
Usually subjects should be between 18-55 yrs old.
Weight of subject is within normal range.
It is important to reduce the intra & inter subject variability
Products are usually administered after overnight fasting & meal taken should standardized.
During the study subject should not taking any other medication .
Subject should not allowed to take any alcoholic or xanthine containing beverages e.g. coffee, tea ,cola ,soft drinks etc.
If subject is smoker then this should be mentioned in their medical history. Reference & Test Product:- : Reference & Test Product:- In bioequivalence study the test product is usually compared with reference product.
Reference product is generally the innovator product (Product of company who 1st invented this product.)
Before proceeding study the both the test product & reference product are tested for in vitro dissolution profile. Evaluation of data:- : Evaluation of data:- Analytical Method:-
The analytical method for measurement of drug must be validated for accuracy, precision ,sensitivity, & specificity.
Only 1 analytical method is used during bioequivalence study because different method may yield different values.
Data should be presented in both graphical & tabulated form for evaluation. Pharmacokinetic evaluation of data : Pharmacokinetic evaluation of data For single dose studies-
Pharmacokinetic analysis include calculation of AUC, Cmax, Tmax.
For multiple dose-
Calculation of steady state AUC, Tmax, Cmax, Normalized Cmax.
Statistical evaluation of data-
This can be done by using analysis of variance (ANOVA) test. Slide 24: Thank you