ba & be_ prashant garg

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Bioavailability andBioavailability and

Bioequivalence studiesBioequivalence studies

PRASHANT KUMAR PRASHANT KUMAR B.PHARMB.PHARM

ISF COLLEGE OF PHARMACYISF COLLEGE OF PHARMACY



v Indicates a measurement of the rate & extent of therapeutically active drugthat reaches the systemic circulation.

v It is the relation in terms of bioavailability, therapeutic response, or a setof established standards of one drug to another.

v Process of dispensing a different brand or unbranded drug product in place of the prescribed drug product

v Substituted drug product contains the same active ingredient or

therapeutic moiety as the same salt or ester in the same dosage form butis made by the different manufacturer.

BioavailabilityBioavailability

EquivalenceEquivalence

Generic substitutionGeneric substitution




v Drug products that contain the same therapeutic moiety but as different salts,esters, and complexes.e.g. Tetracycline phosphate or hydrochloride equivalent to 250 mg Tetracycline

basee.g. extended release & immediate release

Pharmaceutical alternativesPharmaceutical alternatives

v Drug products that contain the same active ingredient (same salt, ester, or chemical form) & are identical in strength/conc., dosage form and route of administration

Pharmaceutical equivalentsPharmaceutical equivalents

v Also chemical equivalentsv Must meet identical standards (strength, quality, purity and identity) butmay differ in characteristics (e.g. color, flavor, shape, packaging,

preservatives)




v Process of dispensing a pharmaceutical alternative for the prescribed drug productv Requires physician’s approval

e.g.. Amoxicillin capsules instead Ampicillin suspension

Pharmaceutic substitutionPharmaceutic substitution

v Drug products containing different active ingredients that are indicated for thesame therapeutic or clinical objective.

Therapeutic alternativesTherapeutic alternatives

v Therapeutic drug products may differ in certain characteristics (e.g. color,flavor, packaging).

Therapeutic equivalentsTherapeutic equivalents

v These drugs are pharmaceutically equivalent and can be expected tohave the same clinical effect and safety profile.




Purpose of Bioavailability StudiesPurpose of Bioavailability Studies

v Ensure the drug product is safe & effective for its labeled indication for use prior to its marketing

Those requiring bioavailability studiesThose requiring bioavailability studies

v Unmarketed drugs which do not have full NDA (new drug application)

v New formulations of active drug ingredients or therapeutic moieties thathave full NDA approval & are approved for marketing.




rug with new NDA rug with new NDA

v : ,Example Metformin antidiabetic drug given as treatment for( ).Polycystic Ovarian syndrome PCOS

v Characterize the essential pharmacokinetics of the active drug( . . & , -ingredient e g rate extent of systemic absorption elimination half

,life rates of excretion and metabolism after single or multiple dose)administration

ew Formulation of a Drug that have ful l NDA approval ew Formulation of a Drug that have full NDA approval

v :Example Enalapril sustained release or sublingual tab in place of,immediate release tab

v Paracetamol capsule in place of paracetamol IV

v To determine the bioavailability and characterize the pharmacokinetics,of the new formulation new dosage form or new salt or ester relative for a reference formulation Bioequivalence studies




Absolute Bioavailability

Ørequires I.V. administrationØRatio of the oral: intravenous AUC values normalized for doseØFabs = (AUC oral / AUC iv)*(Dose iv / Dose oral )

Relative Bioavailability

Øno I.V. referenceØcomparison AUC values (ratio) of different dosage forms /

formulations

ØF rel = (AUC a / AUC b) *(Dose b /Dose a )

Relative andRelative and absolute Bioavailabilityabsolute Bioavailability




Time [hours]

0 4 8 12 16 20 24

C o n

c .

[ m g

/ L ]

0

1

2

3

4

5

Time [hours]0 4 8 12 16 20 24

C o n c .

[ m g

/ L ]

0

1

2

3

4

5

SolutionCapsule

20 mg administered as ani.v. bolus (Diovan)

80 mg given as a solution anda capsule (Diovan)




Time [hours]

0 2 4 6 8 1 0

% o

f f r e m a

i n i n g

t o b e

a b s o r b e

d

0

20

40

60

80

100

SolutionCapsule

A U C

= . *0 2

= . *0 4

= .0 6

0

2

4

6

8

10

12

14

16

I.v. (20 mg) P.O. (80 mg)Capsule

P.O. (80 mg)Solution

*dose - adjusted




:ethods of Assessing Bioavailabil i ty :ethods of Assessing Bioavai labi l i ty

. PLASMA DATA

.a.a tmaxmax - time of peak plasma concentration- time of peak plasma concentration

- the time required to reach the maximum- the time required to reach the maximum drug drug .concentration after drug administration .concentration after drug administration

- ===as rate of absorption tmax- ===as rate of absorption tmax

.b.b Cmaxmax – maximum plasma drug concentration obtained – maximum plasma drug concentration obtained.after the administration of the drug .after the administration of the drug

- indicates that the drug sufficiently and- indicates that the drug sufficiently and systematically absorbed to provide a systematically absorbed to provide a

.therapeutic response .therapeutic response,As,As

- Dose- Dose === Cmax=== Cmax--AA ====bsorptionrate Cmax====bsorptionrate Cmax

--ISF COLLEGE OF PHARMACYISF COLLEGE OF PHARMACY



c.c. AUCAUC Area Under the CurveArea Under the Curve

Area under the plasma level time curveArea under the plasma level time curve

Measure of quantity of drug in the bodyMeasure of quantity of drug in the body◦ If one knows the AUC for a given dose size upon IV administrationIf one knows the AUC for a given dose size upon IV administration

of a drug, the fraction of drug absorbed (F = absoluteof a drug, the fraction of drug absorbed (F = absolute bioavailability) upon EV route of administration can be calculated bioavailability) upon EV route of administration can be calculatedfrom the AUC obtained by the latter routefrom the AUC obtained by the latter route

ØIt is directly proportional to the doseIt is directly proportional to the doseØMeasures the extent of bioavailabilityMeasures the extent of bioavailabilityØUnit: µg/ml.hrs or µg hrs/mlUnit: µg/ml.hrs or µg hrs/ml

ØIndepent of the route of administration and processes of drug elimination asIndepent of the route of administration and processes of drug elimination aslong as the elimination processes do not changelong as the elimination processes do not change




ØR R elative magnitude of the AUC can be obtained by either of theelative magnitude of the AUC can be obtained by either of thefollowing methods:following methods:

1. counting method1. counting method

2. weighing method2. weighing method

ØExact calculation of the AUC is done by either one of the followingExact calculation of the AUC is done by either one of the followingtwo methods:two methods:

1. trapezoidal rule1. trapezoidal rule

2. using blood level equations2. using blood level equations

ØTrapezoidal rule: compute for the individual area of the trapezoids.Trapezoidal rule: compute for the individual area of the trapezoids.ØTotal AUC = 0 → infinityTotal AUC = 0 → infinity

Infinite time – time beyond which the area is insignificantInfinite time – time beyond which the area is insignificant

[AUC][AUC] 00∞∞ = [AUC]= [AUC] 00 tt + [AUC]+ [AUC] tt ∞∞ AuC1 = (AuC1 = ( C0 + C1)C0 + C1) · ( t1 - t0)· ( t1 - t0)

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Informations that we can get from a typical conc-time curveInformations that we can get from a typical conc-time curve

MECMEC – min. conc. required by the receptors to produce the desired – min. conc. required by the receptors to produce the desiredeffecteffect

MTCMTC – min. conc. needed to just barely produce toxic effect – min. conc. needed to just barely produce toxic effect

Desired therapeutic range (therapeutic window)Desired therapeutic range (therapeutic window) – distance between – distance betweenMEC and MTC; it is where the drug produces its characteristic effectsMEC and MTC; it is where the drug produces its characteristic effects

Onset timeOnset time – time required for drug to reach MEC – time required for drug to reach MEC

ØDuration of actionDuration of action – the difference between onset time and the time – the difference between onset time and the timefor the drug to decline back to MEC; length of time the drug levelfor the drug to decline back to MEC; length of time the drug levelremains above MECremains above MEC




2. urine data2. urine data

a.a.Du – cumulative amount of Du – cumulative amount of drug excreted in the urinedrug excreted in the urine- it signifies, how much drug is- it signifies, how much drug is present in the urine present in the urine- directly related to the total- directly related to the total amount of drug absorbed.amount of drug absorbed.

Informations required to prepare/determine the patient’s urine profileInformations required to prepare/determine the patient’s urine profile

1. subjects & dose of drug1. subjects & dose of drug2. determine the total amount of urine collected2. determine the total amount of urine collected3. sample is analyzed for drug content3. sample is analyzed for drug content4. construct a graph of cumulative amount of drug in the urine vs time4. construct a graph of cumulative amount of drug in the urine vs time


v Urinary excretion of the unchanged drug vs time data can be used to

.Estimate the bioavailability of a drug productv .Acc To this method the rate of urinary excretion of a drug is directly proportional to the concentration of the drug in the blood



v umulative amount of drug in urine VS Time umulative amount of drug in urine VS Time




( / )Rate of drug excretion dDu dt vs Time



3.Acute pharmacological effect3.Acute pharmacological effect

1.An established dose-related response curve.2.An easily measurable pharmacological response such as heart rate,

ECG, blood pressure, pupil diameter, etc.

4. clinical response4. clinical resp onse

- toxicity- toxicity- no response- no response- therapeutic failure- therapeutic failure- good therapeutic- good therapeutic

responseresponse




Ø Bioequivalence is a comparison of bioavailability of twoor more product i.e. Formulation containing the same

active ingredient are said to be bio-equivalent if their rate & extent of absorption is same.

Ø One of the best way to compare two product is byclinical studies. But performing clinical studies isextremely dificult& expensive. Hence Bio-equivalencestudies are generally used to compare two products soas to compare their biological equivalence.

Ø Bioequivalence is receiving increasing attention because

of increased availability & importance of generic drugsin today's p’ceutical market.




ØHowever bioequivalence is not straight forward for all the drugs .Many drugs shows bioinequivalence.

Ø In 1973 ad hoc committee on drug product selection of American

Pharmaceutical Association published a list of drug that show bioinequivalence.ØBased on this list drug has been divided into 3 categories

HIGH RISK POTENTIAL

MODERATE RISK POTENTIAL

LOW RISK POTENTIAL

Aminophylline Amphetamine AcetaminophenBishydroxy coumarine Ampicillin CodeineDigoxin Chloramphenicol Hydrochlorothiazide

phenytoin Digitoxin Ephedrine prednisolone Erythromycin Isoniazide prednisone Griesofulvin Meprobamatequinidine Penicillin G Penicillin Vwarfarin Pentobarbital Sulfixazole



ØDifference in predicted clinical response may be due todifference in pharmacokinetics, pharmacodynamics orbioavailability of drug products .

ØBioequivalent drug products that have same systemicdrug bioavailability will have same predictable

response .ØDifference in pharmacodynamics behavior is due to

age, drug tolerance, drug interaction etc.ØBioavaliability of drug may be more during empty

stomachØWhen drug is used on daily basis, nature of an

individuals diet & lifestyle may affect plasma druglevel because variable absorption in the presence of

food.

Bioequivalence StudiesBioeq uivalence Studies


f dB f d i i



Ø

ØBioequivalence is established if the in-vivobioavaliability of test drug product (usuallygeneric product) does not differ significantly inrate & extent of drug absorption, fromreference listed drug (brand name product)administered at same dose, under similarexperimental conditions.

Bases for determiningBases for determining bioequivalencebioeq uivalence




Bioequivalence problem occurs due to following reason-ØActive drug ingredient has low solubility in water . (less than 5 mg/ml)

.

ØDissolution rate is low.ØCertain structural forms of active drug ingredient (e.g. polymorphic

forms, solvates, complexes & crystal modifications) dissolve poorly, thus altering the absorption.

ØDrug product that have high ratio of excipients to active ingredients(e.g. greater than 5:1) .

ØSpecific ingredients such as hydrophilic & hydrophobic excipient &lubricant may interfere with absorption .

ØActive ingredients absorbed in particular segment of GIT.

ØThe degree of absorption of active drug ingredient is poor whenadministered in pure form.ØRapid metabolism in intestinal wall or in liver during absorption

process.ØØ

BIOEQUIVALENCE PROBLEMSBIOEQ UIVALENCE PROBLEMS




Pharmacokinetic StudiesKey Measurements

AUCArea under the

concentration- time curve

Cmax

Maximum concentrationA difference of greater than

20% in C max or the AUCrepresents a significantdifference between thestudy and referencecompounds

T max

Time to maximumconcentration

Study Compound Reference Compound

Time

C o n c e n t r a t i o n

Cmax

Tmax

AUC




This parameter is generally used in bioequivalence studiesof sustained release formulation.

It can be calculated as

%PTF= C max-C minC average

Where C average is Avg Plasma drug conc. During dosing period.

4. Plasma Through fluctuation(%):-




5. T 1/2 :- Elimination half life .It provides informationregarding elimination of drug from the body.

6. Normalized C max:- C max & T max are knownto show significant intersubject variability & hencenormalized C max is used in some cases.

It can be calculated as-Normalized C max= C max

AUC7. Mean residence time(MRT) : It provides an

idea about time a drug molecule spend in the body before itget excreted.


S d P l



1.Title

a) Principle investigator( Study director)

b) Project/protocol number & date.

2.Study objective

3. Study design

a) Design

b) Drug products

1.Test products

2. Reference Product

c) Dosage regimen

d) Sample collection schedule

e) Housing/ confinement

f) Fasting/meal schedule

g) Analytical methods

4. Study populationa) Subjects

b) Subject selection

1. Medical history

2. Physical examination.

3. Laboratory test.

Study Protocol :-




c) Inclusion and exclusion criteriad) Restriction / prohibitions

5. Clinical procedures

A) Dosage and drug administrationB) Biological sampling scheduleC) Activity of subject

6. Ethical ConsiderationA) Basic principlesB) Institutional review boardC) Informed consentD) Adverse reactions

7. Facilities

8. Data analysisA) Analytical validation procedureB) Statistical treatment of data

9. Drug accountability

10. AppendixISF COLLEGE OF PHARMACYISF COLLEGE OF PHARMACY



STUDY DESIGNSTUDY DESIGNv Bioequivalence study should be designed in such away so as to

identify treatment effects that are produced after

administration of products.Two types of design1. Crossover 2. Parallelv Generally crossover is used in practice in this design both test

and reference product are compared in each subject that iseach subject act as his/her own control

v Hence inter subject variable such as age ,weight,metabolism etc. are minimal.

v Because of minimal intersubject variability, crossover design iswidely used for routine studies.v In this design first subjects are randomly divided in to 2 groups

and sequence of drug is randomly assigned.




If there are two formulations – test (T) and reference (R) ; in period 1 , group 1 will receive T followed by R.

Time period between administrations of two formulations

will be sufficiently long considering adequate ‘wash out period’.

Wash out period is essential to ensure complete eliminationof drug before next administration.

10 half lives ensures more than 99% of elimination andhence wash out period should be at least 10 half lives .




Period II will start after completion of wash out period now in period II, group 1 will receive ‘R’ followed by ‘T’ .

If drug require washout period of 7 days then sequence of administration of 2 formulation can be shown as

Thus sequence of administration for group I is T-R & group II is R-T .

Two formulation trial is always a 2 period trial,Thus in period I , 50% subject ( group I) receive T & 50% subject(group II) receive R .

In period II order is reversed

Group Period I (day1) PeriodII (8 day )

I T R II R T




For biequvalence study in human volenteersCompares 3 different drug formulations- A,B,&

C.

In this design , each subject receives each drugproduct only onceAdequate time is provided between

medications for elimination of drug from the

body.In this design each subject is having his /herown control hence subject to subject variationis reduced.

Latin square cross overLatin sq uare cross overdesigndesig n




SUBJECT STUDYPERIOD 1 STUDYPERIOD 2 STUDYPERIOD 3

1 A B C

2 B C A

3 C A B

4 A C B

5 C B A

6 B A C

–A T I N S Q U A R E C R O S S O V E R D E S I G N F O R B I O E Q U I V A L E N C E S T U D Y O F 3 R U G P R O D U C T S I N 6 H U M A N V O L U N T E E R S




ü Subject:-This study is usually performed with healthy volunteers of both

sexes.Usually subjects should be between 18-55 yrs old.Weight of subject is within normal range.It is important to reduce the intra & inter subject variabilityProducts are usually administered after overnight fasting & meal

taken should standardized.During the study subject should not taking any other

medication .Subject should not allowed to take any alcoholic or xanthine

containing beverages e.g. coffee, tea ,cola ,soft drinks etc.If subject is smoker then this should be mentioned in their

medical history.




In bioequivalence study the test product is usually comparedwith reference product.

Reference product is generally the innovator product (Product of company who 1 st invented this product.)

Before proceeding study the both the test product & reference product are tested for in vitro dissolution profile .

Reference & Test Product:-Reference & Test Product:-




Analytical Method:-

ü The analytical method for measurement of drug must be validated for accuracy,precision ,sensitivity, & specificity.

ü Only 1 analytical method is used duringbioequivalence study because differentmethod may yield different values.

ü Data should be presented in both graphical

& tabulated form for evaluation .

Evaluation of data:-Evaluation of data:-




For single dose studies-

Pharmacokinetic analysis include calculation of AUC, Cmax, Tmax.For multiple dose-

Calculation of steady state AUC, Tmax, Cmax,

Normalized Cmax.Statistical evaluation of data-

This can be done by using analysis of variance(ANOVA) test.

Pharmacokinetic evaluation of data




REFERENCESREFERENCES

v . , “ ” ,Ve n ka tesw a rlu V B iop h arm aceu tics an d Ph arm acok in e tics

, , .ed ition 2 0 0 4 Ph arm aM ed p ress H yd erab ad

v . ., . , “B rah m an kar D M Jaisw al B S u n il b ip h arm aceu tics an d- ”, ,p h arm aco kin e tics a trea tise first ed ition 1 9 9 5 Va llab h

, .prakashan N ew D elhiv , ,S h arg e leo n yu p c an d rew ap p lied b iop h arm a ceu tics an d

, .p h arm aco kin e tics th ird ed ition


ba & be_ prashant garg

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