Bioavailability and bioequivalence

Types of bioavailability and concept of equivalence

1. Bioavailability & Bioequivalence Presented by Mr. Naresh Gorantla , M.Pharm .., ( Ph.D ) Assoc professor, Balaji college of Pharmacy, Anantapuramu . 1

2. CONTENTS Definitions Objectives of Bioavailability studies Types of Bioavailability studies Methods of Bioavailability measurement Bioequivalence experimental study designs IVIVC Correlation 2

3. 3 Drug Product Drug in Blood Distribution to Tissue and Receptor sites Metabolism Excretion Bioavailability

4. Bioavailability: Bioavailability is defined as the rate and extent of absorption of unchanged drug from its dosage form. Rate- acute conditions- asthma, pain etc Extent (amount) – chronic conditions- hypertension. Absolute bioavailability: When systemic availability of a drug administered orally is determined in comparison to its I.V. administration, denoted by F . Relative bioavailability: When systemic availability of a drug after oral administration is compared with that of oral standard of the same drug ( Solution or suspension) denoted by Fr . Definitions 4

5. Equivalence: Equivalence is a comparative term used to indicate that 2 or more substances labeled as equivalents are similar to one another with respect to a specific characteristic or function. Chemical equivalence: When two or more drug products contain the same chemical substance as an active ingredient in the same amount it is called chemical equivalence. Pharmaceutical equivalents: These are the drug products containing same API and are identical in strength, dosage form and route of administration. 5

6. 6 Therapeutic equivalence: These are the drug products that are pharmaceutic equivalents that can be expected to have same clinical effect in-vivo. Bioequivalence: It is relative term that denotes drug substance in two or more identical dosage forms reaches the systemic circulation at the same relative rate to the same relative extent . i.e. plasma concentration-time profiles will be identical without significant statistical differences. These are the pharmaceutic equivalents that exhibit comparable Bioavailability under similar conditions.

7. Objectives of Bioavailability studies It is important in the Primary stages of development of dosage form of new drug entity to find its therapeutic utility . Determination of influence of excipients on absorption. Development of new formulations of existing drugs. Control of quality of drug products and to study the influence of processing factors , storage and stability on absorption. Comparison of drug in different dosage forms or same dosage form of different manufacturer. 7

8. 8 Types of Bioavailability studies Two types of Bioavailability studies: First type : Assessment of BA of new Drug product formulations of new drugs. To establish P’kinetic parameters. To know the influence of: Excipients , Processing factors Packaging components Patient related factors on formulation. Second type: Comparison of a test formulation with that of a reference standard dosage form (existing drugs). To develop a new dosage form. To improve an existing dosage form. To compare the P’kinetic profile comparison.

9. Single dose versus multiple dose studies: Single dose bioavailability studies are very common, easy, less exposure to drugs , less tedious. However it is difficult to predict the steady state characteristics and inter subject variability with these studies. Advantages of multiple dose study: -Accurately reflects manner in which drug will be used clinically . -Requires collection of few blood samples . -Drug levels are higher due to cumulative effect and useful for less sensitive analytical methods -Better evaluation of controlled released formulation. -Nonlinearity if present , can be easily determined. 9

10. 10 Healthy subjects versus Patients: Generally bioavailability study should be carried out in patients, as patient get benefited from the study, reflects better therapeutic efficacy, drug absorption pattern in disease state can be studied, avoids ethical quandary of administering drug to healthy subjects. But there are also various drawbacks like, diseases, other drugs, physiological changes, fasting state is difficult etc. Hence usually these studies performed on young (20-40yrs) healthy male adult volunteers (body weight ±10%) under restricted dietary and fixed activity conditions.

11. 11 Methods of Bioavailability measurement 1. Pharmacokinetic methods A. Plasma level time studies B. Urinary excretion studies 2. Pharmacodynamic methods A. Acute pharmacological response B. Therapeutic response

12. Methods of Bioavailability measurement Pharmacokinetic methods 1. Plasma level time studies: most reliable method of choice comparison to urine data method Single dose: serial blood samples collection – 2-3 half lives Plot of concentration vs time For I.V. Sampling started within 5 min and subsequent samples at 15 min intervals For oral dose at least 3 points taken on absorption curve ( ascending part). 12

13. 13 Parameters considered important in plasma level time studies Cmax : It is peak plasma concentration. It increases with dose as well as increase in rate of absorption. Tmax : The peak time at which Cmax attainded . AUC : Area under curve explains about amount of drug. 1. Plasma level time studies:

14. 2. Urinary excretion studies: This method is based on the principle that the urinary excretion of unchanged drug is directly proportional to the plasma concentration of drug. It can be performed if -At least 20% of administered dose is excreted unchanged in urine. The study is useful for Drugs that extensively excreted unchanged in urine eg . Thiazide diuetics Drugs that have urine as site of action eg . Urinary antiseptics like nitrofurontoin . Steps involved: -collection of urine at regular intervals for 7 half lives. Analysis of unchanged drug in collected sample. Determination of amount of drug at each interval and cumulative as well. 14

15. 15 2. Urinary excretion studies: Criteria's must be followed At each sample collection total emptying of bladder is necessary. Frequent sampling is essential in the beginning to compute correct rate of absorption. The fraction excreted unchanged in urine must remain constant. Parameters considered important in Urinary excretion studies ( Dx / dt )max: Maximun urinary excretion rate ( tu )max: Time for maximum excretion rate Xu ∞: Cumulative amount of drug excreted in the urine.

16. 1. Acute pharmacological response: When bioavailability measurement by pharmacokinetic methods is difficult, inaccurate or non reproducible this method is used. Such as ECG, EEG, Pupil diameter etc. It can be determined by dose response graphs . Responses measure for at least 3 half lives. Disadvantages: - Pharmacological response is variable and accurate correlation drug and formulation is difficult. -Observed response may be due to active metabolite. Pharmacodynamic methods 16

17. 17 2. Therapeutic response: This method is based on observing clinical response in patients. Drawbacks: - Quantitation of observed response is too improper. - Theoretically best method, but practically not. - Pharmacodynamics of drug changes with Age, Tolerance and interactions etc. - The patient s receiving more than one drug treatment may be compromised due to drug-drug interaction. Pharmacodynamic methods

18. 18 Bioequivalence studies If a new product is intended to be a substitute for approved medicinal product, then Equivalence must be shown. To ensure the clinical performance of such products, Bioequivalence studies are carried out. To compare the Bioavailability of generic products with the brand products. Bioequivalence experimental study designs 1.Completely randomized design 2.Randomized block design 3.Repeated measures, cross over design 4.Latin square design

19. 19 1.Completely randomized design: All treatments are randomly allocated among all experimental subjects. e.g. If there are 20 subjects, number the from 1 to 20. randomly select non repeating numbers among these labels for the first treatment. And then repeat for all other treatments . Advantages: Easy to construct. C an accommodate any number of treatment and subjects, Simple to analyze. Disadvantages: Suited for few treatments. All subjects must be homogenous other wise random error will occur.

20. 2.Randomized block design: First subjects are divided into homogenous groups , called blocks and then treatments are assigned at random within blocks . Subjects are divided as blocks considering similar background, characteristics. Advantages: Effective and Systematic grouping gives more precise results . No need of maintaining equal sample size, Any number of treatments can be followed. Disadvantages: Missing observations in a block require more complex analysis . 20

21. 3.Repeated measures, carry over design: It is a kind of randomized block design where same subject serves as a block. Same subject utilized repeatedly for each study period so called as repeated measure design. Carry over effects of drugs are measured. Advantages: P recise, Economic, can be performed with few subjects. U seful in observing effects of treatment over time in the same subject at different points of time, and in different subjects over a specified period of time Disadvantages: Cary over effect due to preceding treatment. Wash out period necessary – 10 elimination half lives. 21

22. 22 4.Latin square design: All other above designs are continuous trial. However in Latin square design each subject receives each treatment during the experiment. It is a two factor design ( Rows=Subjects and Columns=Treatments ). Carry –over effects are balanced. Advantages: M inimize variability of plasma profiles and carry-over effects. Small scale experiments can be carried out. Possible to focus on formulation variables. Disadvantages: Long time study . M ore formulations more complex study . S ubject dropout rates are high.

23. 23 In vitro dissolution studies and bioavailability: The physicochemical property of most drugs that has greatest influence on absorption from GIT is dissolution rate. However in vitro dissolution is good substitute for in vivo study in terms of saving cost and time. The best available tool today which can at least quantitatively assure about the bioavailability of drug from its formulation is in vitro dissolution test.

24. 24 In vitro- in vivo correlation ( IVIVC): It is defined as the predictive mathematical model that describes the relationship between in vitro property ( rate & extent of dissolution ) and in vivo response ( plasma drug concentration ). The main objective of developing and evaluating IVIVC is to use dissolution test to serve as alternate for in vivo study in human beings. IVIVC Levels: Level A: The highest category of correlation. It represents point to point correlation between in vitro dissolution and in vivo rate of absorption. Advantages: serves as alternate for in vivo study, change in manf . Procedure or formula can be justified without human studies. Level B: The mean in vitro dissolution time is compare with mean in vivo residence time. It is not point to point correlation . Data can be used for quality control standards. Level C: It is single point correlation. e.g. t 50%, Tmax , Cmax . This level is only useful as guide for formulation development or quality control.

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