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BIOAVAILABILITY,
BIOEQUIVALENCE AND
BCS CLASSIFICATION
Guided By

Pallavi. K M.Pharm,
Department of Pharmaceutics.
Present...
Bioavailability
Objectives of bioavailability
Factors effecting bioavailability
Measurement of bioavailability
Bioequivale...
3
Regulatory Definition

(21 CFR 320.1(a)):

“Bioavailability means the
rate and extent to which the active ingredient or
ac...
Primary stages of development of a suitable dosage form for
new drug entity.
Determination of influence of excipients, pat...
Systemic availability the amount that reaches
systemic circulation is simply known as availability.
Absolute bioavailabili...
Absolute bioavailability

Relative bioavailability
7
Three

major

factors

that

effecting

bioavailability:1. Pharmaceutical factors
2. Patient related factors
3. Routes of ...
Bioavailability

Pharmaceutical
Factors

Physicochemical
Factors

Patient Related
Factors

Route Of
Administration

Pharma...
The methods available are:Pharmacokinetic (Indirect) Method
Pharmacodynamic (Direct) Method.

Selection of method depends ...
T max
Plasma
data

AUC

Indirect
methods

dx u/dt
Urinary
data

Bio
availability
Direct
methods

C max

Acute
pharmacolog
...
Plasma Drug Concentration Vs Time Graph
12
Cmax

- Maximum plasma concentration .

The concentration of drug at therapeutic response is elicited.

Increase with incr...
Rate of urinary excretion of drug versus time plot

14
Maximum urinary excretion rate
It is obtained from peak of plot between rate of urinary
excretion data versus time.

Time ...
Sl. no

Plasma data

Urinary data

1.

Maximum plasma
concentration
C max
Time to maximum
concentration
T max
Area under t...
17
Acute pharmacological response
When bioavailability measurement by pharmacokinetic method is
difficult, an acute pharmacol...
19
Bioequivalence
When the drug from two or more similar dosage form
reaches the general circulation at the same relative rat...
When significant changes are made in the manufacture of the
marketed formulation

When a new generic formulation is tested...
Equivalence

Chemical equivalence
Clinical equivalence

Pharmaceutical Equivalence
Bioequivalence
Therapeutic equivalence
...
Bioequivalence
studies

In vivo

Oral immediate
release

In vitro

Non oral
immediate
release

Modified
release with
syste...
24
The

word

BCS

refers

Biopharmaceutics

Classification System for Drugs, which is based
Aqueous solubility and Permeatio...
Valuable tool for formulation scientist for selection of

design of formulated drug substance.
Efficiency of drug developm...
It’s a theoretical basis for correlating in vitro drug dissolution
with in vivo availability, developed by Dr. Gordon Amid...
Sl.
No

Class

Solubility

Permeabili
ty

Examples

Comment

1.

I

High

High

Metoprolol
Dilitiazem
Verapamil
propranolo...
Sl. no

Class of drug

solubility

permeability

1

Ia

High and site
independent

High and site
independent

2

Ib

High ...
Berstrom

et

al

(2003) modified BCS to six classes

Development is based on calculated surface area, solubility
and perm...
Applications in both pre - clinical and clinical drug

development.
Regulatory toll for replacement of certain be studies....
Solubility profile should be determined

PH range of 1-7.5 at 37

1 c.

The drug is said to be highly soluble in a solutio...
Sl. No

Terms

Parts Of Solute Required To
Dissolve One Part Of Solvent

1.
2.
3.

Very Soluble
Freely Soluble
Soluble

Le...
Highly permeable is said to be when the

extent of absorption is determined 90% or more than it
Human studies include mass...
There are some methods to determine permeability of drug in

GI track include
1. In vivo intestinal perfusion studies in h...
Dissolution class includes IR product following

conditions to be applied
Dissolving not less than 85% amount of drug with...
(FDA Guidelines for industry , 2000; Adomin et al, 1995)

Applicable in NDA’s, ANDA’s and post approval changes.
Primary e...
Conclusions
Every drug in the development process must undergo BABE
studies.

Primary stages of drug development and formu...
Previous GPAT Bits Covered In
This Topic
A drug (200 mg dose) administered in tablet form and as intravenous
injection (50...
Previous GPAT Bits Cover In This
Topic (cont….)
The characteristic of non-linear pharmacokinetics include ( GPAT 2011)
(A)...
Previous GPAT Bits Cover In This
Topic (cont….)
Which conditions does not apply as per Indian lw while conducting
single d...
List Of References
Guidelines for bioavailability and bioequivalence studies,
CDSCO, directorate general of health service...
List Of References (cont…..)
Biopharmaceutics and pharmacokinetics pg no 331-356, - v. venkateshvarulu

Biopharmaceutics c...
Acknowledgement
I sincerely thank and regards

to my guide K. Pallavi, and
other staff members for their
support. I would ...
45
46
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Transcript of "Bioavailability, Bioequivalence and BCS Classification"

  1. 1. BIOAVAILABILITY, BIOEQUIVALENCE AND BCS CLASSIFICATION Guided By Pallavi. K M.Pharm, Department of Pharmaceutics. Presented By 10AB1R0042, Shajeeya Amren. Sk, IV B. Pharm, Vignan Pharmacy College. 1
  2. 2. Bioavailability Objectives of bioavailability Factors effecting bioavailability Measurement of bioavailability Bioequivalence Terms to know in Bioequivalence Types of Bioequivalence studies BCS classification Conclusion Acknowledgement 2
  3. 3. 3
  4. 4. Regulatory Definition (21 CFR 320.1(a)): “Bioavailability means the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.” 4
  5. 5. Primary stages of development of a suitable dosage form for new drug entity. Determination of influence of excipients, patient related factors and interaction with other drugs on the efficiency of absorption. To evaluate the absolute systemic availability of active drug substance from a dosage form. Control quality of drug in early stages of development. Develop new formulation for existing drug. 5
  6. 6. Systemic availability the amount that reaches systemic circulation is simply known as availability. Absolute bioavailability of a drug product may be comparing the respective bioavailabilites after an oral and iv bolus injection. Relative bioavailability is defined as a ratios of bioavilabilities of a drug product and reference standard. 6
  7. 7. Absolute bioavailability Relative bioavailability 7
  8. 8. Three major factors that effecting bioavailability:1. Pharmaceutical factors 2. Patient related factors 3. Routes of administration. 8
  9. 9. Bioavailability Pharmaceutical Factors Physicochemical Factors Patient Related Factors Route Of Administration Pharmaco Technical Factors 9
  10. 10. The methods available are:Pharmacokinetic (Indirect) Method Pharmacodynamic (Direct) Method. Selection of method depends upon :Nature Of The Study Nature Of Dosage Form Analytical Method Development. 10
  11. 11. T max Plasma data AUC Indirect methods dx u/dt Urinary data Bio availability Direct methods C max Acute pharmacolog ical response Clinical response Xu Tu 11
  12. 12. Plasma Drug Concentration Vs Time Graph 12
  13. 13. Cmax - Maximum plasma concentration . The concentration of drug at therapeutic response is elicited. Increase with increase in dose and with an increase in absorption. Tmax - Time to reach maximum concentration Indicates rate of absorption. It decrease as the rate of absorption increases. AUC - Area under the curve. Indicates the extent of drug absorption from a dosage form. The fraction of dose that reaches the systemic circulation. 13
  14. 14. Rate of urinary excretion of drug versus time plot 14
  15. 15. Maximum urinary excretion rate It is obtained from peak of plot between rate of urinary excretion data versus time. Time for maximum excretion rate It is the maximum time required to reach maximum excretion rate. Cumulative amount of drug excreted It is the drug excreted in urine till the drug level falls zero. 15
  16. 16. Sl. no Plasma data Urinary data 1. Maximum plasma concentration C max Time to maximum concentration T max Area under the curve AUC Maximum urinary excretion rate 2. 3. Time to maximum excretion rate Cumulative amount of drug excreted 16
  17. 17. 17
  18. 18. Acute pharmacological response When bioavailability measurement by pharmacokinetic method is difficult, an acute pharmacologic effect are taken into consideration Dose response curve Can be determined by construction of Pharmacological effect Vs Time curve E.g.: pupil diameter, heart rate or BP can be useful as an index of drug bioavailability Clinical response / Therapeutic response Best method Clinical response of the drug for which it is intended to be used is measured Based on clinical response to the drug formulation given to the patients E.g.: for anti-inflammatory drugs, reduction in inflammation is determined 18
  19. 19. 19
  20. 20. Bioequivalence When the drug from two or more similar dosage form reaches the general circulation at the same relative rate and extent then the dosage forms are termed as Bioequivalent. Statistical significant differences are observed in the bioavailability of Bio-inequivalence. two or more drug products, 20
  21. 21. When significant changes are made in the manufacture of the marketed formulation When a new generic formulation is tested against the innovator's marketed product Comparison of availability of drug substance from different dosage forms when changes in formulation have occurred after an innovator product has been approved. Comparison of availability's of same dosage form produced by different manufactures 21
  22. 22. Equivalence Chemical equivalence Clinical equivalence Pharmaceutical Equivalence Bioequivalence Therapeutic equivalence Comparable Dosage Form 22
  23. 23. Bioequivalence studies In vivo Oral immediate release In vitro Non oral immediate release Modified release with systemic action Clinical studies 23
  24. 24. 24
  25. 25. The word BCS refers Biopharmaceutics Classification System for Drugs, which is based Aqueous solubility and Permeation of drug through GI tract. 25
  26. 26. Valuable tool for formulation scientist for selection of design of formulated drug substance. Efficiency of drug development and review process. To Reduces cost and time of approving Scale- up and post approval challenges. Applicable in both pre-clinical and clinical drug development process. Works as a guiding tool in development of various oral drug delivery systems. 26
  27. 27. It’s a theoretical basis for correlating in vitro drug dissolution with in vivo availability, developed by Dr. Gordon Amidon et al(1995) and submitted at FIP, Brazil. Based on Aqueous solubility and intestinal permeability. Classification on Fick’s first law J w = Pw C w Where J w = Drug flux across the GUT wall Pw = Permeability of membrane C w = Drug concentration at GI membrane 27
  28. 28. Sl. No Class Solubility Permeabili ty Examples Comment 1. I High High Metoprolol Dilitiazem Verapamil propranolol Well absorbed, their absorption rate is higher than excretion rate. IVIVC observed 2. II Low High Glibenclamide Phenytoin Danazol Limited by dissolution rate, IVIVC occurs with high dose of drugs. 3. III High Low Cimetidine Acyclovir Neomycin B captropil Absorption is limited by the permeation rate but the drug solvates fast. No IVIVC 4. IV Low Low Chlorothiazide Taxol fuoemide Neither soluble nor absorbed in mucosa. No IVIVC. 28
  29. 29. Sl. no Class of drug solubility permeability 1 Ia High and site independent High and site independent 2 Ib High and site independent Depend on site and narrow therapeutic window 3 II a Low and site independent High and site independent 4 II b Low and site independent Depend on site and narrow therapeutic window 5 V a : acidic Variable variable 6 V b : basic Variable variable 29
  30. 30. Berstrom et al (2003) modified BCS to six classes Development is based on calculated surface area, solubility and permeability. Based on solubility and permeability was classified into 6 classes as low, intermediate and high. Based on surface area Non-polar part - good solubility, Polar part – good permeability. Three compounds are wrongly classified amitryptiline, acyclovir and doxycycline 30
  31. 31. Applications in both pre - clinical and clinical drug development. Regulatory toll for replacement of certain be studies. Reduces the time in the drug development process as time is an important aspect in industry. Leads to direct and indirect savings of pharmaceutical companies. 31
  32. 32. Solubility profile should be determined PH range of 1-7.5 at 37 1 c. The drug is said to be highly soluble in a solution with defined pH when the highest dose is soluble in 250ml of aqueous media over pH range of 1-7.5. Shake flask method is used to for invitro determination of solubility. E.g. Acid or base titration methods. 32
  33. 33. Sl. No Terms Parts Of Solute Required To Dissolve One Part Of Solvent 1. 2. 3. Very Soluble Freely Soluble Soluble Less Than 1 Part 1 To 10 Part 10 To 30 Part 4. 5. 6. Sparingly Soluble Slightly Soluble Very Slightly Soluble Practically Insoluble Or Insoluble 30 To 100 Part 100 To 1000 Part 1000 To 10,000 Part 7. More Than 10,000 Part 33
  34. 34. Highly permeable is said to be when the extent of absorption is determined 90% or more than it Human studies include mass balance studies, absolute bioavailability, intestinal perfusion methods in vivo studies Drug absorption Prediction in humans is by In vitro permeability by intestinal tissue and mono layer of epithelial cells E.g. Caco – 2cells or TC – 7 34
  35. 35. There are some methods to determine permeability of drug in GI track include 1. In vivo intestinal perfusion studies in humans 2. In vivo intestinal perfusion studies in animals 3. In vitro permeation in experiments using excised human or animal tissue intestinal tissue 4. In vitro permeation experiments across monolayer of cultured human intestinal cells. 35
  36. 36. Dissolution class includes IR product following conditions to be applied Dissolving not less than 85% amount of drug with in 30 min Using USP Dissolution apparatus 1 at 100 rpm in a volume of 900ml or less In 0.1 N HCl or simulated gastric fluid or PH 4.5 buffer and PH 6.8 buffer or stimulated intestinal fluid. 36
  37. 37. (FDA Guidelines for industry , 2000; Adomin et al, 1995) Applicable in NDA’s, ANDA’s and post approval changes. Primary evidence of safety and efficacy. Significant in pre and post approval changes in pharmaceutical equivalents. BCS eliminates the need human subjects to reference and test products. 37
  38. 38. Conclusions Every drug in the development process must undergo BABE studies. Primary stages of drug development and formulation of dosage includes Bioavailability. Presently, there is international harmonization of regulatory requirements for bioequivalence studies BCS eliminates unnecessary drugs exposures to healthy subjects and provides economic relief and maintain high public standard for therapeutic equivalence. 38
  39. 39. Previous GPAT Bits Covered In This Topic A drug (200 mg dose) administered in tablet form and as intravenous injection (50 mg dose) showed AUC of 100 and 200 microgram hr/mL, respectively. The absolute availability of the drug through oral administration is : (GPAT 2012) (A) 125% (B) 250 % (C) 12.5% (D) 1.25% Half life is the time it takes for the concentration of drug to halve, no matter what the starting concentration is. If the drug is eliminated by First order kinetics how many half-lives it takes for a drug for total elimination of 97% of drug (GPAT 2010) a) 3 half-lives B) 5 half-lives C) 8 half-lives D) 10 half-lives 39
  40. 40. Previous GPAT Bits Cover In This Topic (cont….) The characteristic of non-linear pharmacokinetics include ( GPAT 2011) (A) Area under the curve is proportional to the dose (B) Elimination half-life remains constant, (C) Area under the curve is not proportional to the dose (D) Amount of drug excreted through remains constant The percentage of a dose of drug product administered via extravascular route that is systemically available as compared to an intravenous dose is referred as (GPAT 2010) A) Absolute bioavailability C) AUC B) Relative bioavailability D) T max 40
  41. 41. Previous GPAT Bits Cover In This Topic (cont….) Which conditions does not apply as per Indian lw while conducting single dose bioavailability study of an immediate release product? (GPAT 2011) a) Sampling Period should be at least three t ½ el b) Sampling should represent pre-exposure, peak exposure and post exposure phases. c) There should be at least four sampling points during elimination phase d) Sampling should be continued till measured AUC is at least equal to 80% of AUC 41
  42. 42. List Of References Guidelines for bioavailability and bioequivalence studies, CDSCO, directorate general of health service, Ministry of family and health welfare, new Delhi. Applied Biopharmaceutics and pharmacokinetics, 6th edition, pg no 431-433 – leon shargel Remington the scientists practice of pharmacy 21st edition, vol 1 1037-1046 Biopharmaceutics and clinical pharmacokinetics 4th edition, pg no 3, 352,171 – robert notori Biopharmaceutics and pharmacokinetics a treatise pg no- 315-363, - DM Bramankar Biopharmaceutics and clinical pharmacokinetics – pg 7-9, 146-175, milo gibadi Martins physical pharmacy and pharmaceutical sciences 6th edition pg no -232 42
  43. 43. List Of References (cont…..) Biopharmaceutics and pharmacokinetics pg no 331-356, - v. venkateshvarulu Biopharmaceutics classification a strategic tool for classifying drug substances ISSN 2230-8407 – rohila seema www.irjponline.com What is bioavailability and bioequivalence Candida agency for drug and technology for health www.cadth.generics/ca Bioavailability and Bioequivalence- Jake J. Thiessen, Ph.D, University of Toront, Canada, Email jj.thiessen@utoronto.ca Bioavailability and Bioequivalence Studies, “ Standard Approach”, www.ivivc.com Bioavailability & bioequivalence trials, Shubha Rani, Ph.D, Synchron Research Services Pvt. Ltd., Ahmadabad, drshubha@synchronresearch.com 43
  44. 44. Acknowledgement I sincerely thank and regards to my guide K. Pallavi, and other staff members for their support. I would also thank my family, friends and finally our beloved Principal Dr. P. Srinivasa Babu. 44
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