Bioavailability

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 2

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4. factors 4

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 5

6. WHY ARE WE CONDUCTING SUCH STUDIES ??? 6

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 8

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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. 12

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 13

14. Parallel design 14

15. Cross over design LATIN SQUARE CROSS OVER DESIGN 15

16. BALANCED INCOMPLETE CROSS OVER DESIGN 16

17. Replicated cross over design 17

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. 18

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. 19

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. 20

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 21

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 22

23. SITUATIONS WHERE MULTIPLE DOSE STUDIES ARE NECESSARY 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). 24

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 : R ivastigmine tartarate (oral cap), Q uatiapine fumerate (oral tab) 25

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 27

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. 28

29. reference D.M . Brahmankar,Sunil B Jaiswal,Biopharmaceutics and Pharmacokinetics 2 nd 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 30

31. THANKUUUUUU……. 31