BIOAVAILABILITY BIOEQUIVALENCE THERAPEUTIC INDEX

The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation
Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations.
The therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals:

1. PHARMACOLOGYPHARMACOLOGY
(405)(405)
Dr. Asra Hameed Dr. Asra Hameed
Pharm.D (JUW) Pharm.D (JUW)
[email protected][email protected]

2. TOPICS
BIOAVAILABILITY
BIOEQUIVALENCE
THERAPEUTIC
INDEX

3. HISTORY: HISTORY:
Phenytoin toxicity in epileptic Phenytoin toxicity in epileptic
patients which occurred in the year patients which occurred in the year
1968 in Australia1968 in Australia
 The differences in the The differences in the
bioavailability observed with bioavailability observed with
different digoxin formulations in the different digoxin formulations in the
year 1971.year 1971.

4. BioavailabilityBioavailability
The extent and rate at which its active The extent and rate at which its active
moiety is delivered from pharmaceutical moiety is delivered from pharmaceutical
form and becomes available in the form and becomes available in the
systemic circulationsystemic circulation
Pharmacokinetics
conc. vs time
C
o
n
c
.
(
m
g
/
L
)
Time (h)
0 25
0.0

5. The “true dose” is not the drug swallowed;
BUT is the drug available to exert its effect.
•?????? Dissolution
•?????? Absorption
•?????? Survive metabolism
May have a drug with very low bioavailability
•?????? Dosage form or drug may not dissolve readily
•?????? Drug may not be readily pass across biological
membranes (i.e. be absorbed)
•?????? Drug may be extensively metabolized during
absorption process (first-pass, gut wall, liver)
Important component of overall variability
•?????? Variable bioavailability may produce variable
exposure
Why do we care about BIOAVAILABILITYWhy do we care about BIOAVAILABILITY??

6. Route Bioavailability (%)Route Bioavailability (%)
Characteristics Intravenous 100 (by definition) Characteristics Intravenous 100 (by definition)
Most rapid onset (IV)Most rapid onset (IV)
 Intramuscular 75 to = 100 Large volumes Intramuscular 75 to = 100 Large volumes
often feasible; may be (IM) painful often feasible; may be (IM) painful
Subcutaneous 75 to = 100 Smaller volumes Subcutaneous 75 to = 100 Smaller volumes
than IM; may be painful (SC)than IM; may be painful (SC)
 Oral (PO) 5 to < 100 Most convenient; first Oral (PO) 5 to < 100 Most convenient; first
pass effects may be significant pass effects may be significant
Rectal (PR) 30 to < 100 Less first-pass Rectal (PR) 30 to < 100 Less first-pass
effects than oraleffects than oral
 Inhalation 5 to < 100 Often very rapid onset Inhalation 5 to < 100 Often very rapid onset
Transdermal 80 to = 100 Usually very slow Transdermal 80 to = 100 Usually very slow
absorption; used for lack of first-pass effects; absorption; used for lack of first-pass effects;
prolonged duration of actionprolonged duration of action

7. Objectives of bioavailability
studies:
Development of new formulation.
Determination of influence of excipients,
patient related factors and possible
interaction with other drugs on the efficiency
of absorption.
 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.
Primary stages of the development of a
suitable dosage form for a new drug entity.

8. Significance of Significance of
Bioavailability : Bioavailability : 
Drugs having low therapeutic index, e.g. cardiac
glycosides, quinidine, phenytoin etc.
Drugs whose peak levels are required for the effect
of drugs, e.g. phenytoin, phenobarbitone, primidone,
sodium valporate, anti-hypertensives,antidiabetics
and antibiotics.
 Drugs that are absorbed by an active transport,e.g.
amino acid analogues, Purine analogues etc.
Drugs which are disintegrated in the alimentary canal
and liver,e.g.chiorpromazine etc. or those which
under go first pass metabolism.
 Formulations that give sustained release of drug,
formulations with smaller disintegration time than
dissolution rate and drugs used as replacement
therapy also warrant bioavailability testing.
In addition, any new formulation has to be tested for
its bioavailability profile.

9. ABSOLUTE
BIOAVAILABILITY
The systemic availability of a drug
administered orally is determined in
comparison to its iv administration.
Characterization of a drug's
absorption properties from the e.v.
site.
 F = AUCev AUCiv

10. RELATIVE BIOAVAILABILITY
The availability of a drug product as
compared to another dosage form
or product of the same drug given
in the same dose.
 Characterization of absorption of a
drug from its formulation.
 Fr=AUCA AUCB

11. DETERMINATION OF
BIOAVAILABILITY
It is determined by It is determined by
comparing plasma comparing plasma
levels of a drug after levels of a drug after
a particular route of a particular route of
administration (e.g. administration (e.g.
oral administration) oral administration)
with plasma drug with plasma drug
level achieved by IV level achieved by IV
injection- in which all injection- in which all
the agent rapidly the agent rapidly
enters the enters the
circulation.circulation.

12. When the drug is given orally, only part When the drug is given orally, only part
of the administered dose appears in the of the administered dose appears in the
plasma. By plotting plasma plasma. By plotting plasma
concentrations of the drug versus time, concentrations of the drug versus time,
one can measure the area under the one can measure the area under the
curve (AUC). curve (AUC).
This curve reflects the extent of This curve reflects the extent of
absorption of the drug. absorption of the drug.
[Note: By definition, this is 100 percent [Note: By definition, this is 100 percent
for drugs delivered IV.] for drugs delivered IV.]
Bioavailability of a drug administered Bioavailability of a drug administered
orally is the ratio of the area calculated orally is the ratio of the area calculated
for oral administration compared with for oral administration compared with
the area calculated for IV injection the area calculated for IV injection

13. The key parameters for determining The key parameters for determining
bioavailabilitybioavailability
 1. AUC: The AUC is proportional to the 1. AUC: The AUC is proportional to the
total amount of drug reaching the total amount of drug reaching the
systemic circulation, and thus systemic circulation, and thus
characterizes the extent of absorption. characterizes the extent of absorption.
2. Cmax: Gives indication whether drug 2. Cmax: Gives indication whether drug
is sufficiently absorbed systemically to is sufficiently absorbed systemically to
provide a therapeutic response.provide a therapeutic response.
 3. Tmax: The Tmax reflects the rate of 3. Tmax: The Tmax reflects the rate of
drug absorption, and decreases as the drug absorption, and decreases as the
absorption rate increases.absorption rate increases.

14. B. Factors that influence bioavailabilityB. Factors that influence bioavailability
First-pass hepatic metabolism: When a drug is absorbed across the First-pass hepatic metabolism: When a drug is absorbed across the
GI tract, it enters the portal circulation before entering the systemic GI tract, it enters the portal circulation before entering the systemic
circulation (see Figure 1.3). If the drug is rapidly metabolized by the circulation (see Figure 1.3). If the drug is rapidly metabolized by the
liver, the amount of unchanged drug that gains access to the liver, the amount of unchanged drug that gains access to the
systemic circulation is decreased. Many drugs, such as propranolol systemic circulation is decreased. Many drugs, such as propranolol
or lidocaine, undergo significant biotransformation during a single or lidocaine, undergo significant biotransformation during a single
passage through the liver.passage through the liver.
Solubility of the drug: Very hydrophilic drugs are poorly absorbed Solubility of the drug: Very hydrophilic drugs are poorly absorbed
because of their inability to cross the lipid-rich cell membranes. because of their inability to cross the lipid-rich cell membranes.
Paradoxically, drugs that are extremely hydrophobic are also poorly Paradoxically, drugs that are extremely hydrophobic are also poorly
absorbed, because they are totally insoluble in aqueous body fluids absorbed, because they are totally insoluble in aqueous body fluids
and, therefore, cannot gain access to the surface of cells. For a and, therefore, cannot gain access to the surface of cells. For a
drug to be readily absorbed, it must be largely hydrophobic, yet drug to be readily absorbed, it must be largely hydrophobic, yet
have some solubility in aqueous solutions. This is one reason why have some solubility in aqueous solutions. This is one reason why
many drugs are weak acids or weak bases. There are some drugs many drugs are weak acids or weak bases. There are some drugs
that are highly lipid-soluble, and they are transported in the that are highly lipid-soluble, and they are transported in the
aqueous solutions of the body on carrier proteins such as albumin.aqueous solutions of the body on carrier proteins such as albumin.
Chemical instability: Some drugs, such as penicillin G, are unstable Chemical instability: Some drugs, such as penicillin G, are unstable
in the pH of the gastric contents. Others, such as insulin, are in the pH of the gastric contents. Others, such as insulin, are
destroyed in the GI tract by degradative enzymes.destroyed in the GI tract by degradative enzymes.
Nature of the drug formulation: Drug absorption may be altered by Nature of the drug formulation: Drug absorption may be altered by
factors unrelated to the chemistry of the drug. For example, particle factors unrelated to the chemistry of the drug. For example, particle
size, salt form, crystal polymorphism, enteric coatings and the size, salt form, crystal polymorphism, enteric coatings and the
presence of excipients (such as binders and dispersing agents) can presence of excipients (such as binders and dispersing agents) can
influence the ease of dissolution and, therefore, alter the rate of influence the ease of dissolution and, therefore, alter the rate of
absorption.absorption.

15. FACTORS INFLUENCING
BIOAVAILABILITY:
Three distinct factors are involved Three distinct factors are involved
to influencing bioavailability.to influencing bioavailability.
Pharmaceutical factorsPharmaceutical factors
Patient related factorsPatient related factors
Route of administrationRoute of administration

16. 1.Pharmaceutical factors:1.Pharmaceutical factors:
Physicochemical properties of the Physicochemical properties of the
drug.drug.
1. Particle size 1. Particle size
2. Crystalline structure2. Crystalline structure
 3. Salt form3. Salt form
Formulation and manufacturing
variables.
 1.Disintegration and dissolution time 1.Disintegration and dissolution time
2.Pharmaceutical ingredients2.Pharmaceutical ingredients
 3.Special coatings3.Special coatings
 4.Nature and type of dosage form.4.Nature and type of dosage form.

17. 2. Patient related factors:2. Patient related factors:
Physiologic factors.
1.Variations in pH of GI fluids 1.Variations in pH of GI fluids
2.Gastric emptying rate 2.Gastric emptying rate
3. Intestinal motility 3. Intestinal motility
4. Presystemic and first-pass metabolism 4. Presystemic and first-pass metabolism
5. Age, sex 5. Age, sex
6. Disease states6. Disease states

Interactions with other
substances.
1. Food 1. Food
2. Fluid volume 2. Fluid volume
3. Other drugs 3. Other drugs

18. 3. Route of administration:3. Route of administration:
1.Parentral administration1.Parentral administration
2.Oral administration2.Oral administration
3.Rectal administration 3.Rectal administration
4.Topical administration4.Topical administration

19. BioequivalenceBioequivalence
Two related drugs are bioequivalent if they Two related drugs are bioequivalent if they
show comparable bioavailability and show comparable bioavailability and
similar times to achieve peak blood similar times to achieve peak blood
concentrations. concentrations.
Two related drugs with a significant Two related drugs with a significant
difference in bioavailability are said to be difference in bioavailability are said to be
bioinequivalent.bioinequivalent.

20. BioequivalenceBioequivalence
0
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Time (hours)
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Test/Generic
Reference/Brand

21. Goals of BE
Ultimate: Bioequivalence studies impact of
changes to the dosage form process after
pivotal studies commence to ensure product on
the market is comparable to that upon which
the efficacy is based
Establish that a new formulation has therapeutic
equivalence in the rate and extent of absorption to
the reference drug product.
Important for linking the commercial drug product to
clinical trial material at time of NDA
Important for post-approval changes in the marketed
drug formulation

22. Pharmaceutical Pharmaceutical
EquivalentsEquivalents
Drug products are considered Drug products are considered
pharmaceutical equivalents if they pharmaceutical equivalents if they
contain the same active ingredient(s), contain the same active ingredient(s),
have the same dosage form and route of have the same dosage form and route of
administration, and are identical in administration, and are identical in
strength or concentration strength or concentration
Equivalent products contain the same Equivalent products contain the same
amount of ingredient in the same dosage amount of ingredient in the same dosage
form but may differ in characteristics, form but may differ in characteristics,
such as shape, release mechanisms, and such as shape, release mechanisms, and
packagingpackaging

23. Pharmaceutical Pharmaceutical
Alternatives Alternatives
Drug products are considered pharmaceutical Drug products are considered pharmaceutical
alternatives if they contain the same alternatives if they contain the same
therapeutic moiety, are different salts, esters, therapeutic moiety, are different salts, esters,
or complexes of the same moiety, are or complexes of the same moiety, are
different dosage forms, or are different different dosage forms, or are different
strengthsstrengths
 Other pharmaceutical alternatives Other pharmaceutical alternatives
Different dosage forms and strengths within a Different dosage forms and strengths within a
single product line by a single manufacturer single product line by a single manufacturer
Extended-release formulations when Extended-release formulations when
compared with immediate- or standard-compared with immediate- or standard-
release formulationsrelease formulations

24. THERAPEUTIC
EQUIVALENCE
Two similar drugs are
therpeutically equivaient if they
have comparative efficacy and
safety.
Two drugs that are
bioequivalent may not be
therapeutically equivalent.

25. Therapeutic index
The therapeutic index of a drug is the ratio
of the dose that produces toxicity to the
dose that produces a clinically desired or
effective response in a population of
individuals:
where TD50 = the drug dose that produces
a toxic effect in half the population and
ED50 = the drug dose that produces a
therapeutic or desired response in half the
population.
 The therapeutic index is a measure of a
drug's safety, because a larger value
indicates a wide margin between doses
that are effective and doses that are toxic.

27. Narrow therapeutic index:Narrow therapeutic index:
having little difference between toxic and having little difference between toxic and
therapeutic doses therapeutic doses
Large therapeutic index:Large therapeutic index:
A high therapeutic index is preferable to a low A high therapeutic index is preferable to a low
one: this corresponds to a situation in which one: this corresponds to a situation in which
one would have to take a much higher amount one would have to take a much higher amount
of a drug to do harm than the amount taken to of a drug to do harm than the amount taken to
do good. do good.

28. Determination of therapeutic indexDetermination of therapeutic index
The therapeutic index is determined by measuring The therapeutic index is determined by measuring
the frequency of desired response, and toxic the frequency of desired response, and toxic
response, at various doses of drug. By convention, response, at various doses of drug. By convention,
the doses that produce the therapeutic effect and the doses that produce the therapeutic effect and
the toxic effect in fifty percent of the population are the toxic effect in fifty percent of the population are
employed; these are known as the ED50 and TD50, employed; these are known as the ED50 and TD50,
respectively.respectively.
In humans, the therapeutic index of a drug is In humans, the therapeutic index of a drug is
determined using drug trials and accumulated determined using drug trials and accumulated
clinical experience. These usually reveal a range of clinical experience. These usually reveal a range of
effective doses and a different (sometimes effective doses and a different (sometimes
overlapping) range of toxic doses.overlapping) range of toxic doses.

29. Although some drugs have narrow Although some drugs have narrow
therapeutic indices, they are routinely therapeutic indices, they are routinely
used to treat certain diseases.used to treat certain diseases.
 Several lethal diseases, such as Several lethal diseases, such as
Hodgkin's lymphoma, are treated with Hodgkin's lymphoma, are treated with
narrow therapeutic index drugs; however, narrow therapeutic index drugs; however,
treatment of a simple headache, for treatment of a simple headache, for
example, with a narrow therapeutic index example, with a narrow therapeutic index
drug would be unacceptable. drug would be unacceptable.
Figure shows the responses to warfarin, Figure shows the responses to warfarin,
an oral anti-coagulant with a narrow an oral anti-coagulant with a narrow
therapeutic index, and penicillin, an therapeutic index, and penicillin, an
antimicrobial drug with a large therapeutic antimicrobial drug with a large therapeutic
index.index.

31. WarfarinWarfarin
Warfarin (example of a drug with a
small therapeutic index):
As the dose of warfarin is increased, a As the dose of warfarin is increased, a
greater fraction of the patients respond greater fraction of the patients respond
(for this drug, the desired response is a (for this drug, the desired response is a
two-fold increase in prothrombin time) two-fold increase in prothrombin time)
until eventually, all patients respond.until eventually, all patients respond.
 However, at higher doses of warfarin, a However, at higher doses of warfarin, a
toxic response occurs, namely a high toxic response occurs, namely a high
degree of anticoagulation that results in degree of anticoagulation that results in
hemorrhage.hemorrhage.
When the therapeutic index is low, it is When the therapeutic index is low, it is
possible to have a range of possible to have a range of
concentrations where the effective and concentrations where the effective and
toxic responses overlap. toxic responses overlap.

32. That is, some patients hemorrhage, That is, some patients hemorrhage,
whereas others achieve the desired whereas others achieve the desired
two-fold prolongation of prothrombin two-fold prolongation of prothrombin
time. time.
Variation in patient response is, Variation in patient response is,
therefore, most likely to occur with a therefore, most likely to occur with a
drug showing a narrow therapeutic drug showing a narrow therapeutic
index, because the effective and toxic index, because the effective and toxic
concentrations are similar.concentrations are similar.
 Agents with a low therapeutic index—Agents with a low therapeutic index—
that is, drugs for which dose is critically that is, drugs for which dose is critically
important—are those drugs for which important—are those drugs for which
bioavailability critically alters the bioavailability critically alters the
therapeutic effects.therapeutic effects.

34. PenicillinPenicillin
Penicillin (example of a drug with a
large therapeutic index):
 For drugs such as penicillin, it is For drugs such as penicillin, it is
safe and common to give doses in safe and common to give doses in
excess (often about ten-fold excess (often about ten-fold
excess) of that which is minimally excess) of that which is minimally
required to achieve a desired required to achieve a desired
response. response.
In this case, bioavailability does not In this case, bioavailability does not
critically alter the therapeutic critically alter the therapeutic
effects.effects.

35. MARIYAM ATHERMARIYAM ATHER
CONCLUSION

36. BIOAVAILABILIT
Bioavailability is the fraction of Bioavailability is the fraction of
administered drug that reaches the administered drug that reaches the
systemic circulation.systemic circulation.
 Bioavailability is expressed as the Bioavailability is expressed as the
fraction of administered drug that gains fraction of administered drug that gains
access to the systemic circulation in a access to the systemic circulation in a
chemically unchanged form.chemically unchanged form.
 For example, if 100 mg of a drug are For example, if 100 mg of a drug are
administered orally and 70 mg of this administered orally and 70 mg of this
drug are absorbed unchanged, the drug are absorbed unchanged, the
bioavailability is 0.7 or seventy percent. bioavailability is 0.7 or seventy percent.

37. BIOEQUIVALENCE
Two related drugs are bioequivalent Two related drugs are bioequivalent
if they show comparable if they show comparable
bioavailability and similar times to bioavailability and similar times to
achieve peak blood concentrations. achieve peak blood concentrations.
Two related drugs with a significant Two related drugs with a significant
difference in bioavailability are said difference in bioavailability are said
to be bioinequivalent.to be bioinequivalent.

38. THERAPEUTIC
INDEX
The therapeutic index of a drug is
the ratio of the dose that
produces toxicity to the dose that
produces a clinically desired or
effective response in a population
of individuals.