comparison of bio availability of single doses v/s multiple dose formulations

1. Presented By
Arantha.J.Joseph
1st Year Mpharm
Dept.Of Pharmaceutics 1

2. COMPARISON OF BIOAVAILABILITY OF
SINGLE DOSE VS MULTIPLE DOSE
FORMULATIONS
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3. 3

4. FACTORS
Pharmaceutical
factors.
Patient related
factors.
Route of administration.
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5. COMPARATIVE BIOAVAILABILITY:
When the systemic availability of a drug after oral
administration is compared with that of an oral standard of
the same drug
 Fr
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6. WHY ARE WE
CONDUCTING SUCH
STUDIES ???
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7. 7
 Determination of influence of excipients, patient related
factors and possible interactions.
 Development of new formulation of existing drug.
 Control of quality of drug product during early stages of
marketing .
Comparison of availability of a drug substance from
different dosage forms or from the same dosage form
produced by different manufacturers.

8. SINGLE DOSE VS MULTIPLE DOSE
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9. 9

10. 10

11. 11

12. STUDY DESIGNS
Selection of study design is based upon .
 Number of formulations to be compared.
 Characteristics of the drug and disposition.
 Study objective.
 Availability of the subject.
 Inter and intra subject variability.
 Duration of study or the number of periods allowed.
 Cost of adding a subject relative to that of
adding one period.
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13. BIOAVAILABILITY STUDIES
1. Parallel design
2. Cross over design
i. Latin square cross over design
ii. Balanced incomplete block
design
iii .Replicated cross over design
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14. PARALLEL DESIGN
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15. CROSS OVER DESIGN
LATIN SQUARE CROSS OVER DESIGN
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16. BALANCED INCOMPLETE CROSS OVER DESIGN
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17. REPLICATED CROSS OVER DESIGN
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18. GENERAL APPROACHES FOR SINGLE
DOSE STUDY
Generally the highest marketed strength should
be administered as a single unit.
If necessary for analytical reasons multiple units
of highest strength can be administered.
 Providing the total single dose remains within
the labelled range.
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19. The lot numbers of both test and reference listed.
Expiration date for the reference product should be
stated.
 The drug content of the test product shouldn’t
differ from reference product by more than 5%.
An adequate washout period should (more than
5half life) separate each treatment.
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20. Prior and during each study phase
Subjects should be allowed water as desired
except for 1hr before .
After drug admn; be provided standard meals
not less than 4hrs.
 Abstain from alcohol for 24hrs prior to each
study period and until after the last sample from
each period is collected.
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21. MULTIPLE DOSE
Very potent or toxic drugs
Single dose study cannot be conducted in healthy
volunteers – tolerability reasons
Multiple dose study can be used
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22. In rare situations problems of sensitivity of the analytical
method sufficiently precise plasma concentration
measurements after single dose administration.
Where the con at steady state is sufficiently high to
measure.
Multiple dose study - alternative
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23. 23

24. Problems in plasma concentration measurement after
single dose .
Intra individual variability in the plasma
concentration or disposition rate is inherently large.
In the case of extended release formulations (in
addition to single dose studies).
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25. If special dosage regimens such as
loading dose or twice a day dosing
are to be used.
Differences in rate of absorption but
not in the extent of absorption
Eg : Rivastigmine tartarate(oral
cap), Quatiapine fumerate(oral tab)
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26. 26
conclusion

27. ADVANTAGES
SINGLE DOSE
Very common.
Easy.
Less exposure to lugs.
Less tedious.
MULTI DOSE
More accurate clinical
description.
Fewer blood samples are
required .
Drug levels are high
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28. DISADVANTAGES
SINGLE DOSE
Cannot predict steady
state predictions.
Inter subject variability
cannot be predicted.
Long sampling periods.
MULTIDOSE
Tedious
Costly and difficult to
conduct.
Poor compliance by
subjects .
More exposure to test
drugs hence potential for
ADR.
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29. REFERENCE
D.M .Brahmankar,Sunil B Jaiswal,Biopharmaceutics and
Pharmacokinetics 2nd edition ,pg no 315-363.
Attachment 1 of Division-Notification 0229 No. 10 of the
Pharmaceutical and Food Safety Bureau, dated February
29, 2012
Xue-Jia Zhai, MD, Ye Yu, MD, Fen Chen, MS, Yong-Ning
Lu, MD, ; Comparative Bioavailability and Tolerability of
Single and Multiple Doses of 2 Diclofenac Sodium
Sustained-Release Tablet Formulations in Fasting, Healthy
Chinese Male Volunteers ,Sciecedirect ;1-09-2013
29

30. Henry.J.Malinowski;Bioavailability and Bioequivalence
testing; Remington’s textbook of pharmaceutics ;
volume 1; chapter 53 ; pg no 995 -1004
Applied Biopharmaceutics and Pharmacokinetics-5th
edition by Leon Shargel, Susanna Wu-PONG, Andrew
B.C.YU. Page no; 453-498
Alfredo García ; Design of Bioequivalence Studies
WHO Workshop on Assessment of Bioequivalence
Data, 31 August – 3 September, 2010, Addis Ababa
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31. THANKUUUUUU…….
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