Bioavailability and Bioequivalence

bioavailability and bioequivalence

1. 1 Syed Rashed Faizan Mehdi BIOAVALABILITY & BIOEQUIVALENCE

2. 2 TABLE OF CONTENTS S.NO CONTENTS PAGE NO 1 Need for BA and BE 3-4 2 When should BE conducted 5-6 3 Bioavailability 7 4 Factors influencing BA 8-10 5 Objectives 11 6 Types of BA Absolute BA Relative BA 12 13-16 17-20 7 Single Vs Multiple dose study 21 8 Human volunteer Vs Patient 24 9 Measurement of BA 26 10 Absolute BA by I.V route is not always 100% 38

3. 3 TABLE OF CONTENTS S.NO CONTENTS PAGE NO 11 Why may a BA higher than 100% be compared 39 12 Bioequivalence 40 13 Types of bioequivalence 41

4. 4 Which formulation has higher bioavailability?

5. N EE D F O R B I O A V A I L A B I L I T Y – B I O E Q UI V A L E NC E S T U D IE S : Bioavailability To evaluate the absolute systemic availability of oral, topical, intramuscular, or any other dosage forms. To determine if bioavailability parameters are linear over the proposed clinical dosage range. To estimate inter and intra subject variability To study food effects Bioequivalence Surrogate for therapeutic equivalence to enable switch ability An appropriate measure for the quality control of the products in vivo

6. When should bioequivalence studies conducted: When a generic formulation is tested against an innovator brand. When the proposed dosage form is different from that used in clinical trails. When significant changes are made in the manufacture of the marketed formulation

7. 7 Introduction to bioavailability The therapeutic effectiveness of a dosage form, intended to treat a systemic condition, is the ability to deliver the active ingredient to its site of action at a rate and amount sufficient to cause the desired response. This property of a dosage form is referred as physiologic availability , biologic availability or bioavailability Bioavailability captures two essential features , namely how fast the drug enters the systemic circulation ( rate of absorption ) and how much of the nominal strength enters the body ( extent of absorption) Bioavailability of a drug can be determined by testing the drug in biological fluids drawn at different intervals.

8. 8 Bioavailability It is defined as the rate and extent at which the un changed drug is delivered to the systemic circulation from a dosage form. The rate or rapidity with which a drug is absorbed is an important consideration when a rapid onset of action is desired as in the treatment of acute conditions like asthma attack, pain. A slower absorption rate is desired when the aim is to prolong the duration of action or to avoid the adverse effects. Extent of absorption is significance in treatment of chronic conditions like hypertension, epilepsy etc. If the size of the dose to be administered is same , then bioavailability of drug form its dosage form depends upon 3 major factors Pharmaceutical factors. Patient related factors. Route of administration. 8

9. Three distinct factors are involved to influencing bioavailability. These are: 1.Pharmaceutical factors: physicochemical properties of the drug. 1. Particle size 2. Crystalline structure 3. Salt form Formulation and manufacturing variables. 1.Disintegration and dissolution time 2.Pharmaceutical ingredients 3.Nature and type of dosage form 9

10. 2. Patient related factors Physiologic factors. 1.Variations in pH of GI fluids 2.Gastric emptying rate 3. Intestinal motility 4. Presystemic and first-pass metabolism 5. Age, sex 6. Disease states Interactions with other substances. 1. Food 2. Fluid volume 3. Other drugs 10

11. 3. Route of administration: 1.Parentral administration 2.Oral administration 3.Rectal administration 4.Topical administration The influence of route of administration on drug’s bioavailability generally follows this order: Parenteral > oral > rectal > topical. Within parenteral route, i.v. injection of a drug results in 100% bioavailability as the absorption process is bypassed. In case of oral route, the dose available to the patient is called Bio available dose which is often less than the administered dose. Therefore, the bio-available fraction F, refers to the fraction of administered dose that enters the systemic circulation. The value ranges between 0 to 1. F =   11

12. OBJECTIVES OF BA STUDIES: Bioavailability studies are important in the… Primary stages of development of a suitable dosage form for a new drug entity. Determination of influence of excipients , patient related factors & possible interaction with other drugs on the efficiency of absorption. Development of new formulations of the existing drugs. Control of quality of a drug product during the early stages of marketing in order to determine the influence of processing factors, storage & stability on drug absorption. 12

13. Types of bioavailability study design Absolute VS. Relative Bioavailability Single dose VS. Multiple dose study Human volunteers-healthy subjects VS. Patients 13

14. 14 1. Absolute bioavailability It is the comparison of bioavailabilities of drug upon oral and IV (Intra Vascular) administration. Intravenous dose is selected as a standard because the drug is administered directly into the systemic circulation and avoids absorption (100% bioavailability) The oral solution cannot be taken used as standard dose due to the following demerits. All the pharmacokinetic parameters cannot be determined It is difficult to differentiate between the dose unabsorbed and metabolized

15. 15 Area under concentration curve (AUC) Absolute bioavailability – IV bolus

16. 16 Area under concentration curve (AUC) Absolute bioavailability – oral dosage form (A)

17. 17 For the same dose(IV vs. Oral), the bioavailability is given by: Absolute bioavailability of IV and Oral dosage form F =  

18. 18 The relative bioavailability is comparison of the bioavailability of an orally administered drug with the bioavailability of an oral standard (suspension or solution) of the same drug. 1. Relative bioavailability

19. 19 Area under concentration curve (AUC) Relative bioavailability for oral dosage form standard

20. 20 Area under concentration curve (AUC) Relative bioavailability for oral dosage form test

21. 21 For the same dose (Oral vs. Oral) The bioavailability is given by: F =   Relative bioavailability for oral dosage form standard and test

22. 22 S i n g l e do s e b io a v a i l a b i li t y s t u d i es a r e v e r y c o m m o n , e a s y , o ff er l ess e x p o s u re a n d l ess t e d i ou s . Bu t , i t ’ s d i f f i c u l t t o p r e di ct t h e s t e a d y s t a te c h a r a c te r i s t i cs a n d in te r s u b j e ct v a r i a b i l i ty b y t h i s me t h o d . 2. Single dose VS. Multiple dose.

23. 23 Multiple dose study is difficult to control(poor subject compliance), exposes the subject to more drug , highly tedious and time consuming but has several advantages like: More accurately reflect the manner in which the drug should be used. Better evaluation of performance of a controlled release formulation is possible. Nonlinearity in pharmacokinetics, if present, can be easily detected. Easy to predict the peak & valley characteristic of the drug since the bioavailability is determined at steady – state. 2. Single dose VS. Multiple dose.

24. 24 Requires collection of fewer blood samples . Can be ethically performed in patients because of the therapeutic benefit to the patient. Multiple dose continued. In multiple dose study, one must ensure that steady state level has been reached . For this, the drug should be administered for 5-6 elimination half lives before collecting blood sample.

25. 25 Ideally, bioavailability studies should be carried out in patients for whom the drug is intended to be used because of the apparent advantages 1. The patient will be beneficial from the study. 2. Reflects better therapeutic efficacy of a drug. 3. Drug absorption pattern in disease states can be evaluated . 4. Avoids the ethical requirements of administering drugs to the healthy subjects. In multiple dose study, they prefer patients rather than healthy humans 3. Human volunteers-healthy subject VS. Patient

26. 26 But, the drawbacks of using patients as volunteers are – disease , other drugs the patients may be taking, physiological changes, etc. may modify drug absorption pattern. studies should be performed in young – 20 to 40 years, healthy, male, adult volunteers, body weight within a range ± 10%, under restricted dietary and fixed activity condition . The consent of volunteers must be obtained and they must be informed about the conditions to be followed during the course of studies – to abstain from any other medication for at least 2 weeks and to fast overnight prior to and for a minimum of 2-4 hours post dosing as well as possible hazards if any. 3. Human volunteers-healthy subject VS. Patient

27. 1. Pharmacokinetics ( Indirect method) – the assumption that the pharmacokinetics profile reflects the therapeutics effectiveness of a drug plasma level-time studies urinary excretion studies 2 Pharmacodynamics ( Direct method) – Measurement of drug effects on a physiological process as a function of time. Acute pharmacological studies Therapeutic response Measurement of bioavailability

28. 28 The methods is based on assumption that two dosage form that exhibit superimposable plasma level-time profile in a group of subjects should result in identical therapeutic activity with the “ single dose study ” The method involves collection of serial blood samples for periods of 2-3 biological half-lives after drug administration, their analysis for drug concentration and making a plot of concentration VS. corresponding time of sample collection to obtain the plasma level-time profile. The three parameters of plasma level-time studies which are considered important for determining bioavailability are- 1) C max :- The peak plasma concentration that gives an indication whether the drug is sufficiently absorbed systematically to provide a therapeutic response Plasma level time studies:

29. 29 C max is a function of both rate and extent of absorption C max will increase with an increase in the dose as well as with an increase in the absorption rate Plasma level time studies:

30. 30 T max :- The peak time that gives an indication of the rate of absorption. It decreases as the rate of absorption increase. AUC:- The area under the plasma level time curve that gives a measure of the extent of absorption or the amount of drug that reaches the systemic circulation . The extent of bioavailability can be determined by the following equations Plasma level time studies: F =   F =  

31. 31 With the multiple dose studies , drug administration for at least 5 biological half lives . A blood sample should be taken at the end of previous dosing interval and 8 to 10 sample after the administration of next dose. The extent of bioavailability can be given as Plasma level time studies: F =   τ = Tau is a dosing interval Bioavailability can also be determined from the peak plasma concentration at steady state C ss , max according to eq F =  

32. 32 Plasma level time studies:

33. 33 In this method of assessing bioavailability is based on the principle that the urinary excretion of unchanged drug is directly proportional to the plasma concentration of the drug. A rule of thumb that at least 20% of administered dose is excreted unchanged in the urine then only the urinary excretion data should be conducted. The study is particularly useful for Drug extensively excreted unchanged in the urine eg:sulphonamides and thiazide diuretics Drug that have urine as the site of action eg:nitrofurantoin and hexamine Urinary excretion studies:

34. 34 Method involves Collection of urine at regular intervals for time-span equal to 7 biological half-lives . Analysis of unchanged drug in the collected sample . Determination of amount of drug excreted in a each interval and cumulative amount excreted Urinary excretion studies: The three major parameters examined in urinary excretion data obtained with a single dose study are D xu / dt max:- The maximum urinary excretion rate It is obtained from the peak of plot between rate of excretion versus midpoint time of urine collection period

35. 35 Urinary excretion studies: Tu max :- The time for maximum excretion rate It is analogous to the T max of the plasma level data Its value decreases as the absorption rate increases The extent of bioavailability can be determined by the following equations X ∞ u :- The cumulative amount of drug excreted in the urine It is related to the AUC of plasma level data and increases as the extent of absorption increases F =   F =  

36. 36 Urinary excretion studies: With the multiple dose study to steady state, the equation for computing bioavailability is F =   Where is the amount of drug excreted unchanged during a single dosing interval at steady state   T i me of s a mp l e c o l le c t i on

37. 37 When bioavailability measurement by pharmacokinetic methods is difficult, inaccurate or non-reproducible . Acute pharmacological effect like EEG reading ECG Pupil diameter The methods requires measurement of response for at least 3 biological half-lives of the drug Disadvantages: Accurate correlation between measured response and drug available from the formulation is difficult Pharmacodynamic methods Acute pharmacological response method

38. 38 Theoretically the most definite, this method is based on observing the clinical response to a drug formulation given to patient suffering from disease for which it is intended to be used. Quantitation of observed response is to improper . Many patient receive more than one drug. Pharmacodynamic methods Therapeutic response method

39. 39 By assumption, a drug administered by the i.v. route has 100%bioavailability. This is true only if the active substance reaches arterial blood without loss. Drugs are generally administered by the i.v. route and have first to cross the pulmonary circulation before gaining access to arterial blood . Lungs can be the site of an extensive first-pass effect and reduce drug availability. This is the case for prostaglandins or some amines. Absolute bioavailability by the I.V. route is not always 100%

40. 40 Bioavailabilities higher than 100% are regularly reported, which is conceptually impossible . The reasons for this are numerous, including experimental errors and nonfulfilment of the assumption for computation of absolute bioavailability. Why may a bioavailability higher than 100% be computed

41. 41 Bioequivalence Bioequivalence indicates that the drug from two or more similar dosage forms gets absorbed at the same rate and to the same extent into the systemic circulation. In simpler terms, the dosage forms are said to be bioequivalent when their plasma level time profile are identical. Generally the rate and extent of absorption of bioequivalent drug product differ by 20% or less.

42. 42 Chemical equivalence: It indicates that two or more drug products that contain the same labelled chemical substance as an active ingredient in the same amount. Bioequivalence: It is a relative term which denotes that the drug substance in two or more identical dosage forms , reaches the systemic circulation at the same relative rates and to the same relative extent i.e their plasma concentration time profiles will be identical without the significant statistical differences . Any statistically significant difference observed in the bioavailability of the drug product is an indication of bioequivalence. Therapeutic equivalence: This term indicates that two or more drug products that contain the same therapeutically active ingredient elicit identical pharmacological effects and can control the disease to the same extent. Types of Bioequivalence

43. 43 Clinical equivalence: when t h e s ame d r u g f r o m 2 o r m o re d o s a g e f o r m s g iv es id e n t i c a l i n vi v o e ff e c ts as meas u r e d b y ph a r mac o l o g i c a l r e s p o n se o r b y c on tr o l ov er a s y m p t o m o r a d i sease. Pharmaceutical equivalence: The term implies that two or more drug products are identical in strength, quality, purity, content uniformity, disintegration and dissolution characteristics . They may however differ in containing different excipients. Types of Bioequivalence

44. 44 References: 1) Biopharmaceutics and pharmacokinetics by Bhramankar . 2) Bioequivalence and statistics in clinical pharmacology Series editors: N. Keiding, B. Morgan, T. Speed, P. van der Heijden 3)Biopharmaceutics and pharmacokinetics by venkateshwaluru