BA and BE studies

Types of Bioavailability and bioequivalence studies

1. BIOAVAILABILITY & BIOEQUIVALENCE STUDIES UNDER THE GUIDANCE OF : PRESENTED BY : Prof . R. NAGARAJU M.HARITHA Institute of Pharmaceutical Technology, Sri Padmavati Mahila Visvavidyalayam ( Women’s University) Tirupati . A.P 1

2. 2 Bioavailability is a term used to indicate the Fractional extent to which a dose of drug reaches to its site of action or a biological fluid, from which the drug has access to its site of action. OR It is defined as an Rate and Extent of absorption of unchanged drugs from its dosage form. Bioavailable Fraction: Bioavailable dose F = Administered dose BIOAVAILABILITY :

3. Considerations IN IN-VIVO Bioavailability Study Design : There are 2 types of bioavailability 1) Absolute Bioavailability 2) Relative Bioavailability 3

4. Absolute Bioavailability : When the systemic availability of the drug after oral administration is compared to its IV administration is called as Absolute Bioavailability. Absolute bioavailability after oral drug administration using plasma data can be determined as following : (AUC)oral F = (AUC)iv 4

5. It is used to characterize a drug inherent absorption properties from the extravascular site. EXAMPLE : Absolute Bioavailability of Nimodipine for different route of administration Oral – 1.17% Nasal – 67.4 % IV - 100% An Absolute Bioavailability of 1 or 100 % indicates complete absorption by comparing reference standard as an IV dose. 5

6. F may be expressed as fraction ( or ) as percentage multiplying F*100 absolute availability using urinary excretion data can be determined. (Du)oral \dose oral F = ( Du)iv \ dose iv Du = Total amount of drug excreted in urine. 6

7. RELATIVE BIOAVAILABILITY : When the systemic availability of the drug after oral administration is compared with that of oral standard of same drug (such as aqueous or non aqueous solutions , suspensions) is referred as relative or comparative bioavailability. It is used to characterize absorption of drug from its formulation. (AUC) A Fr = (AUC)B 7

8. EXAMPLE: Comparision between Capsule Amoxicillin & Suspension Amoxicillin. When different doses are administered a correction for the size of dose is made , as the following equation. (AUC)A \dose A Relative availability = ( AUC) B \ dose B 8

9. The total amount of drug excreted in the urine is collected as the percentage availability using urinary excretion data can be determined as follows % Relative availability = { (Du) A / (Du) B } Relative bioavailability 1or 100 % indicates that bioavailability of drug from both dosage forms is same but does not indicates complete absorption. 9

10. BIOEQUIVALENCE STUDIES DEFINITION : It refers to the drug substance in two or more identical dosage forms , reaches systemic circulation at the same rate to the relative extent. i.e. their plasma concentration time profiles will be identical without significant statistical difference. 10

11. ADVANTAGES: Minimizes the effect of inter subject variability. It minimizes the carry over effect. Requires less number of subjects to get meaningful results. DISADVANTAGES: Requires long time to complete the studies. Increase in study periods leads to high subject dropouts. Completion of studies depends on number of formulations evaluated in the studies. 11

12. OBJECTIVES: If a new product is intended to be substitute for an approves medicinal product as a pharmaceutical equivalent or alternative ,equivalence with this product should be shown or justified. Bioequivalence studies are conducted if there is : A risk of bio inequivalence and /or A risk of pharmacotherapeutic failure or diminished clinical safety. 12

13. Some of the important terms relevant in this context will be defined. Equivalence: It is a relative term that compares drug product with respect to a specific characteristic or function to defined set of standards. There are several types of equivalences: A. Chemical Equivalence B. Pharmaceutical Equivalence C. Bioequivalence D. Therapeutic Equivalence 13

14. Types of Bioequivalence Studies Bioequivalence can be demonstrated either: In vivo or In vitro In vivo 1. Oral immediate release products with systemic action- Indicated for serious conditions requiring assured response. Narrow therapeutic margin. Unfavorable physicochemical properties eg. Low solubility , metastable modifications. 14

15. Non – oral immediate release products. Modified release products with systemic action. In vivo bioequivalence studies are conducted in the usual manner i.e pharmacokinetic & pharmacodynamic methods. PHARMACOKINETIC METHODS a) Plasma level time studies b) Urinary Excretion studies PHARMACODYNAMIC STUDIES a) Acute pharmacological response b) Therapeutic response 15

16. In vitro Bioequivalence studies The drug product differs only in strength of active substance it contains some of the following conditions : a) Pharmacokinetics are linear b) The qualitative composition is the same. c) The ratio between the active substances and the excipients is the same. d) Both products are produced by the same manufacturer at the same production site. e) The product contains active ingredient in the same concentrations as the approved drug product. 16

17. The drug product meets all the following requirements: a) The product is in the form of solution or solubilized form . b) The product contains active ingredient in the same concentration as the approved drug product. The drug product has been slightly reformulated or the manufacturing method has been slightly modified by the original manufacturers. An acceptable IVIVC and the invitro dissolution rate of new product is equivalent with that of already approved medicinal product. 17

18. DESIGN OF BIOEQUIVALENCE STUDIES: P R O T O C O L 18

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21. Analytical Methods Must be accurate Should be with appropriate precision Measure the actual concentration of the active drug or active metabolites achieved in the body. REFERENCE STANDARD Reference standard is generally a formulation currently marketed with a fully approved NDA for which there are valid scientific safety and efficacy data. Usually innovators or brand drug. 21

22. EXTENDED RELEASE FORMULATIONS: Product has claimed controlled release characters No occurrence of dose dumping. Steady state is equivalent to currently marketed extended release formulation. COMBINATION OF DRUG PRODUCTS To determine the rate & extent of absorption of each active ingredient administered concurrently as separate single ingredient preparations. 22

23. STUDY DESIGNS Fasting study Food intervention study Multiple - dose 23

24. 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 concentration- time profile. Subjects should be fasting condition – at least 10 hours before drug administration and 4 hours after administration 24

25. FOOD INTERVENTION STUDY These studies are conducted after high fat & high calorie meal. Meal is given 30 minutes before dosing. No food is given for at least 4 hours after administration. Done for modified release dosage forms. 25

26. MULTIPLE - DOSE Done for extended release drug products Done in addition to the fasting & food intervention study Sampling done similar to fasting study. 26

27. CROSS OVER DESIGNS Each subject receives the test & reference drug product. Eg : Latin square designs Each subject receives only one drug product Adequate wash-out periods is provided between drugs. ADVANTAGES: Subject – to – subject variation is reduced All patients don ot receive same drug product on the same day. 27

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30. PERIOD- time period in which a study is performed Two period study- performed on 2 different days separated by a washout period – generally 10 elimination half lives . SEQUENCE – no.of different orders in the treatment groups in a study For eg : two sequence , two period study would be designed as follows 30

31. EVALUATION DATA 1.ANALYTICAL METHOD Must be validated for accuracy, precision , sensitivity& specifity Using more than one analytical method for a study is not valid – different methods may yield different results. Plasma concentration - time curve should be available. 31

32. 2.PHARMACOKINETIC EVALUATION OF DATA Area under curve to the last quantifiable concentration ( AUC 0-t ) Area under curve to infinity ( AUC 0-∞ ) T max C max Elimination rate constant ,k Elimination half –life t 1/2 32

33. STATISTICAL EVALUATION OF DATA ANALYSIS OF VARIANCE (ANOVA) When Dp <0.05, the difference between 2 drug product is not “statistically significant” TWO ONE SIDED TESTS PROCEDURE Demonstrate if bioavailability of the drug from test formulation is too low or high or in comparison to reference drug Evaluation of confidence limits – 90% ± 20% 33

34. CONCLUSION: Concept of bioequivalence has been adopted by the pharmaceutical industry and national regulatory authorities through out the world for over 20 years. There is continuing attempt to understand & develop more sufficient & scientifically valid approaches to assess bioequivalence of various dosage forms including some of the tough complex special dosage forms. Absolute & Relative biaoavailability shows drug availability according to their standards 34

35. REFERENCES Lachmann / Lieberman’s, The theory and practice of industrial pharmacy . Brahmankar DM, Jaiswal SB, Biopharmaceutics and Pharmacokinetics.. www.google.com 35

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