2. BIOEQUIVALENCE STUDIES
• To compare the bioavailability of the generic drug
product to the brand-name product.
• Bioequivalent drugs that have same systemic
bioavailability will have same predictable drug
response.
• Still, variable response may occur due to age, drug
tolerance, drug interactions or disease states.
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3. Determining Bioequivalence
• Test drug is bioequivalent if in vivo bioavailability of
test (generic drug) do not differ significantly
(statistically insignificant) compared to reference
(brand drug).
• Done by measuring plasma drug concn, urinary
excretion rates, pharmacodynamic effects, etc.
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4. Neccessity to Establish Bioequivalence
• Marketed drug products do not give comparable
therapeutic effects.
• Narrow therapeutic ratio; requires careful dosing.
• Serious adverse effect on the treatment (if not
bioequivalent).
• Low water solubility of active drug.
• Slow dissolution rate.
• High ratio of excipients to active ingredients (>5:1).
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5. Neccessity to Establish Bioequivalence
Contd…
• Active drug absorbed in particular segment of the GI
tract .
• Absorption is less than 50%.
• Rapid first-pass metabolism.
• Drug is subject to dose-dependent kinetics.
• Drug is rapidly metabolized or excreted.
• Drug requires special coatings such as enteric
coating.
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6. DESIGN OF BIOEQUIVALENCE STUDIES
The test and reference drug formulations must
contain:
pharmaceutically equivalent drug,
in the same dose strength,
in similar dosage forms (eg, immediate release or
controlled release), and
given by the same route of administration.
Approval from Institutional Review Board (IRB) of the
testing unit.
Consists of both single dose & multiple dose studies.
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7. I. Title
A. Principal investigator
(study director)
B. Project/protocol
number and date
II. Study objective
III. Study design
A. Design
B. Drug products
1. Test product(s)
2. Reference product
C. Dosage regimen
D. Sample collection schedule
E. Housing/confinement
F. Fasting/meals schedule
G. Analytical methods
IV. Study population
A. Subjects
B. Subject selection
1. Medical history
2. Physical examination
3. Laboratory tests
Elements of a Bioavailability Study
Protocol
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8. C. Inclusion/exclusion criteria
1. Inclusion criteria
2. Exclusion criteria
D. Restrictions/prohibitions
V. Clinical procedures
A. Dosage and drug
administration
B. Biological sampling
schedule and handling
procedures
C. Activity of subjects
VI. Ethical considerations
A. Basic principles
B. Institutional review board
C. Informed consent
D. Indications for subject
withdrawal
E. Adverse reactions and
emergency procedures
VII. Facilities
VIII. Data analysis
A. Analytical validation
procedure
B. Statistical treatment of
data
IX. Drug accountability
X. Appendix
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9. Analytical Methods
• Must be accurate.
• Of sufficient sensitivity to measure small changes.
• Should be with appropriate precision.
• Measure the actual concentration of the active drug
or active metabolite(s), achieved in the body.
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10. Reference Standard
• One formulation of the drug is chosen as reference
standard against which all other formulations of the
drug are compared.
• Reference drug should be administered by the same
route as other drug formulations.
• Reference standard is generally a formulation
currently marketed with a fully approved NDA for
which there are valid scientific safety and efficacy
data.
• Usually innovator’s or brand drug.
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11. Extended-Release Formulations
• Done in order to ensure that:
1. Product has claimed controlled-release characters.
2. No occurrence of dose-dumping.
3. Steady state is equivalent to currently marketed
extended release formulation.
4. Consistent pharmacokinetic performance b/w units.
New extended-release product compared with
existing non-controlled release products.
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12. Combination drug products
• To determine the rate & extend of absorption of each
active ingredient.
• And to determine if it is equivalent to the rate and
extent of absorption of each active ingredient
administered concurrently as separate single-
ingredient preparations.
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13. Study Designs
1. Fasting study
2. Food intervention study
3. Multiple-dose (steady-state) study
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14. 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 concn—time profile.
• Subjects should be in fasting condition—at least 10
hrs before drug administration and 4 hrs after
administration.
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15. Food Intervention Study
• Studies are conducted after high-fat and high-calorie
meal.
• Subjects should be in fasting condition at least 10 hrs
before drug administration.
• Meal is given 30 minutes before dosing.
• No food given for at least 4 hrs after administration.
• Done for modified-release dosage forms.
• And for immediate-release forms if bioavailabilty is
affected by food (e.g.. Ibuprofen, naproxen).
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16. Multiple-Dose (Steady-State) Study
• Done for oral extended-release (controlled-release)
drug products.
• Done in addition to the fasting & food intervention
study.
• Three consecutive Cmin measured on three consec:
days to determine steady state.
• Sampling done similar to fasting study.
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17. Crossover Designs
• Each subject receives the test & reference drug
product.
• Eg. Latin-square crossover designs.
• Each subject receives each drug product only once.
• Adequate wash-out period is provided b/w drugs.
Advantages:
Subject-to-subject variation is reduced.
All patients do not receive same drug product on the
same day.
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20. • Period—time period in which a study is performed.
• Two-period study – performed on 2 diff. days separated
by a washout period—generally about 10 elimination
half-lives.
• Sequence—no. of diff orders in the treatment groups
in a study.
• For e.g., a two-sequence, two-period study would be
designed as follows:
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21. EVALUATION OF DATA
1. Analytical Method
• Must be validated for accuracy, precision, sensitivity,
& specificity.
• Using more than one analytical method for a study is
not valid—different methods may yield diff. results.
• Data presented in both tabulated and graphic form
for evaluation.
• Plasma drug concentration–time curve should be
available.
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22. EVALUATION OF DATA
2. Pharmacokinetic Evaluation of the Data
• Area under the curve to the last quantifiable
concentration (AUC0–t)
• Area under the curve to infinity (AUC0–∞)
• T max
• C max
• elimination rate constant, k
• elimination half-life, t 1/2
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23. EVALUATION OF DATA
3. Statistical Evaluation of the Data
• (a) Analysis Of Variance (ANOVA)
When p ≤ 0.05, the diff b/w 2 drug products is not
“statistically significant”.
• (b) Two One-Sided Tests Procedure
Demonstrate if bioavailability of the drug from Test
formulation is too low or high in comparison to
reference drug.
Evaluation of confidence limits—90% ± 20%
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24. Waivers of In Vivo Bioequivalence Studies
• Done when 2 drug products are:
In same dosage form.
Proportionally similar in active & inactive ingredients.
Differ only in strengths of the medication.
• Bioequivalence study of lower strength(s) can be
waived.
• Only in vitro dissolution test is required to establish
bioequivalency.
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25. REFERENCES
• Shargel. L, Applied Biopharmaceutics and
Pharmacokinetics, 5th edition, Mc Graw Hill,
Singapore, 2005, pp 460-475
• Madan. P. L, Biopharmaceutics and Pharmacokinetics,
1st edition, Jaypee, New Delhi, 2000, pp 141-155
• Chatwal. G. R, Biopharmaceutics and
Pharmacokinetics, 1st edition, Himalaya, new Delhi,
2003, pp 201-215
• Brahmankar. D. M, Biopharmaceutics and
Pharmacokinetics—A Treatise, 1st editon, Vallabh
Prakashan, 2006, pp290-296
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