Assessment of Bioavailability

1. Bioavailability and Bioequivalence
Dr. Nilesh S Kulkarni
PES Modern college of Pharmacy (For Ladies)
Moshi, Pune

2. Dose regimen ResponseExposure
Site of action
Pharmacokinetics Pharmacodynamics
Prepared By Nilesh S KUlkarni

3. Drug Product
Drug in
Blood
Distribution to
Tissue and Receptor sites
MetabolismExcretion
Easy to understand using intravenous
route
No absorption phase, Simple to follow
Concepts clear with less assumptions
Need some math background algebra,
log scale, Simple linear Equations etc
complex math (differential equations,
statistical concepts etc) for Modeling,
Population PK, PK-PD etc.
Basic Concepts bioavailability
Prepared By Nilesh S KUlkarni

4. • Following dose administration, we
need to follow its drug’s disposition
to understand its PK characteristics.
• This is achieved by analyzing the
changes of the drug and/or its
metabolite in blood, plasma, urine
etc.
• A simple approach is to generate
Drug Concentration-Time profile
Dosing
Sampling at
Pre-determined
Time intervals
Bio-analytics
Conc. vs time
profiles
Prepared By Nilesh S KUlkarni

5. Bioavailability and Its Assessment
Bioavailability: The rate and extent to which the parent
compound reaches the general circulation.
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.
The evaluation of BA is made by data comparison of the BA from tested
product and the BA data from a solution, suspension or IV dosage
form.
Prepared By Nilesh S KUlkarni

6. What are the aims of the bioavailability studies?
• Absolute Bioavailability
Compares the bioavailability (estimated as area under the curve, or AUC) of the
active drug in systemic circulation following non-intravenous administration (i.e.,
after oral, rectal, transdermal, subcutaneous administration), with the
bioavailability of the same drug following intravenous administration( By
definition, when a medication is administered intravenously, its bioavailability is
100%).
• . For example, the formula for calculating F for a drug administered by the oral
route (po) is :
Prepared By Nilesh S KUlkarni

7. • It is used to choice the best formulation in a group of
different dosage forms.
• It measures the bioavailability of a certain drug when
compared with another formulation of the same drug,
usually an established standard (solution or other one),
or through administration via a different route. The area
under the curve (AUC), Cmax and Tmax are used to
make comparisons.
Choice of the best formulation: Relative Bioavailability
Prepared By Nilesh S KUlkarni

8. Prepared By Nilesh S KUlkarni

9. Single Dose Vs Multiple dose study
Single Dose
Less tedious
Less exposure to drug
In case of single dose study,
Difficult to predict steady state characteristics of drug
& intersubject variability with single dose study.
Multiple Dose
 More tedious
More exposure to drug,
 Time consuming.
Advantages of Multiple Dose Study
 More accurately reflects the manner in which drug should be used.
 Easy to predict peak & valley characteristics of drug.
 Requires collection of fewer blood samples.
 Better evaluation of performance of a controlled release dosage formulation is
possible.
 Nonlinearity in pharmacokinetic is easily detected, if present.
 Ethically performed in patients.
Prepared By Nilesh S KUlkarni

10. Measurement of bioavailability
Quantitative Estimation of Bioavailability
A) Pharmacokinetic
a) Plasma-level time studies ( Cmax, tmax, AUC )
b) Urinary Excretion data
B) Pharmacodynamic study
a) Acute Pharmacologic response
b) Therapeutic response
Prepared By Nilesh S KUlkarni

11. In Single Dose study, extent of bioavailability is determined by,
(AUC) oral Div
(AUC) iv Doral
F =
(AUC) test Dstd
(AUC) std Dtest
Fr =
In Multiple dose study
Urinary excretion data
Urinary excretion of unchanged drug is directly proportional to plasma concentration of drug
Prepared By Nilesh S KUlkarni

12. Pharmacodynamic
a) Acute Pharmacologic response
When BA measurement is difficult, inaccurate, no reproducible by PK method,
then acute pharmacologic effects such as change in electrocardiogram, change in
pupil diameter is related with the time course of given drug.
Disadvantage – more variable accurate correlation between response and drug
available from formulation is difficult.
b) Therapeutic response
Observing clinical response to drug formulation given to patient suffering from
disease to which it is intended to be used.
Disadvantage- observed response is too improper to allow for reasonable
assessment of relative bioavailability between two dosage forms.
Prepared By Nilesh S KUlkarni

13. Bioequivalence: Background
• Using bioequivalence as the basis for approving generic copies of
drug products was established by the “Drug Price Competition and
Patent Term Restoration Act of 1984,” also known as the Waxman-
Hatch Act.
• This Act expedites the availability of less costly generic drugs by
permitting FDA to approve applications to market generic versions
of brand-name drugs without conducting costly and duplicative
clinical trials.
• At the same time, the brand-name companies can apply for up to
five additional years longer patent protection for the new medicines
they developed to make up for time lost while their products were
going through FDA's approval process. Brand-name drugs are
subject to the same bioequivalence tests as generics upon
reformulation.
Prepared By Nilesh S KUlkarni

14. • Definition - CFR 320.1
It is the absence of significance difference in the
rate and extent to which active ingredient or active
moiety in pharmaceutical equivalent or
pharmaceutical alternative becomes available at
the site of drug action when administered at the
same molar dose under similar conditions in an
appropriately designed study
• Note: BE has a specific definition and regulatory
requirements. BE is not the same as the BA
Prepared By Nilesh S KUlkarni

15. To compare a definitive dosage form (industrial batch!) with
the dosage form used in clinical trials developed and
evaluated ( Relative Bioavailability).
To compare 2 dosage forms (containing “Old C.E”.)
administered by the same way, but with formulation or
Manufacturing Process different ,in the same company.
To compare 2 dosage forms (containing “Old C.E” ) of
formulation and Manuf. Process unknown: ”Generics", copies
of an Innovator (considered as “reference”).
Prepared By Nilesh S KUlkarni

16. When do we do BE studies ?
Change of formulations (capsules to tablet)
Generic Formulations
Change of Process or manufacturing site (some times)
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17. BA BE testing
Following Aspects are important with respect to bioequivalence testing
1. Significance
2. Study design
3. Regulatory consideration
Prepared By Nilesh S KUlkarni

18. 1. Significance
 Significant problem not observed in BA and BE of those drugs where 75 %
drug is dissolved in water or 0.1 N HCl in 45 min.
 BA BE testing has significant importance in case of drugs which have a
narrow theraputic index. E.g. digoxin, phenytoin, theophyllin.
 USP has pointed 4 formulation related problems causing bioequivalence
problems .
1. Particle size of API
2. Excessive amount of lubricant
3. Polymer used for coating
4. Insufficient quantity of disintegrant
Some examples of drugs with bioequivalence problem, warfarin, theophyllin,
acetazolamide.
Precautions are required while using generic substitutes.
Prepared By Nilesh S KUlkarni

19. Therefore to reduce these problems USFDA has published
Approved drug products with therapeutic Equivalence Evaluation
list. This provides information on multiple source drugs that are
therapeutically equivalent or in equivalent . (This book is referred as
FDA orange book).
BA BE studies have significance in,
1. Establishment of pharmacokinetic parameter.
2. Regulatory Requirements need different types of bioavailability and
bioequivalence studies to be conducted.
3. Development of formulation studies, Process variable and effect of
formulation.
Prepared By Nilesh S KUlkarni

20. Study Design
The different experimental designs for BA BE studies are as follows,
1. Parallel design
2. Complete cross over design
a. Two period, two sequence cross over design
b. Three period, three sequence cross over design
c. Latin square design
3. Balanced incomplete block design
Prepared By Nilesh S KUlkarni

21. 1. Parallel Design
Two groups -one group of subjects receives on formulations,
one group receives other formulation which is to be compared.
Drawback- intra subject and inter subject variations are not avoided,
not recommended .
2. Complete cross over design
Generally, variability within the subject is higher than that between the
subjects, Complete cross over design are used to overcome these
variability. Each subject receives each formulation over a period
separated by washout period.
Prepared By Nilesh S KUlkarni

22. Two period, two sequence cross over design -
For two formulation
Washout period of 5 half lives.
Three period, three sequence cross over design-
Formulation differences with three treatment groups
Sequence Period
1 A B
2 B A
Sequence Period
1 2 3
1 A B C
2 B C A
3 C A B
4 B A C
5 C B A
6 A C bPrepared By Nilesh S Kulkarni

23. • Latin square Cross over design
Comparison of more than two formulations. In this design, each
formulation occurs once in each subject and once in each week.
Thus number of subjects used are in multiple of the no. of
formulations being tested.
Sequence AB followed by Sequence BA
Limitations
cross over design are not suitable for testing of 3, 4 or large no. of
formulations because it requires long time. Ethically it is not advisable.
Subject Period
1 2
1,2,3,4,5,6 A B
7,8,9,10,11,12 B A
Prepared By Nilesh S KUlkarni

24. Balanced Incomplete Block design
Each formulation occurs same no. of time and every pair of formulations
occurs together in the same number of subjects.
Subject Period
1 2
1 A B
2 B C
3 D B
4 B A
5 A C
6 D C
7 C A
8 C D
9 A D
10 B D
11 C B
12 D A
Prepared By Nilesh S Kulkarni