This document discusses key topics related to pharmacology including bioavailability, bioequivalence, and therapeutic index. It provides background on how bioavailability was studied initially due to toxicity issues with certain drugs. Factors that influence bioavailability include pharmaceutical factors like formulation, patient factors like metabolism, and route of administration. Bioequivalence compares the bioavailability of two drugs to determine if they are therapeutically equivalent. The therapeutic index is the ratio of toxic to therapeutic doses - a higher index is preferable as it means toxicity occurs at a much higher dose level.

1. PHARMACOLOGYPHARMACOLOGY
(405)(405)
Dr. Asra HameedDr. Asra Hameed
Pharm.D (JUW)Pharm.D (JUW)
asra_hameed1@hotmail.comasra_hameed1@hotmail.com

2. TOPICS
BIOAVAILABILITY
BIOEQUIVALENCE
THERAPEUTIC
INDEX

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

4. BioavailabilityBioavailability
 The extent and rate at which its activeThe extent and rate at which its active
moiety is delivered from pharmaceuticalmoiety is delivered from pharmaceutical
form and becomes available in theform and becomes available in the
systemic circulationsystemic circulation
Pharmacokinetics
conc. vs time
Conc.(mg/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 volumesIntramuscular 75 to = 100 Large volumes
often feasible; may be (IM) painfuloften feasible; may be (IM) painful
 Subcutaneous 75 to = 100 Smaller volumesSubcutaneous 75 to = 100 Smaller volumes
than IM; may be painful (SC)than IM; may be painful (SC)
 Oral (PO) 5 to < 100 Most convenient; firstOral (PO) 5 to < 100 Most convenient; first
pass effects may be significantpass effects may be significant
 Rectal (PR) 30 to < 100 Less first-passRectal (PR) 30 to < 100 Less first-pass
effects than oraleffects than oral
 Inhalation 5 to < 100 Often very rapid onsetInhalation 5 to < 100 Often very rapid onset
 Transdermal 80 to = 100 Usually very slowTransdermal 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 ofSignificance 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 byIt is determined by
comparing plasmacomparing plasma
levels of a drug afterlevels of a drug after
a particular route ofa particular route of
administration (e.g.administration (e.g.
oral administration)oral administration)
with plasma drugwith plasma drug
level achieved by IVlevel achieved by IV
injection- in which allinjection- in which all
the agent rapidlythe agent rapidly
enters theenters the
circulation.circulation.

12.  When the drug is given orally, only partWhen the drug is given orally, only part
of the administered dose appears in theof the administered dose appears in the
plasma. By plotting plasmaplasma. By plotting plasma
concentrations of the drug versus time,concentrations of the drug versus time,
one can measure the area under theone can measure the area under the
curve (AUC).curve (AUC).
 This curve reflects the extent ofThis 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 administeredBioavailability of a drug administered
orally is the ratio of the area calculatedorally is the ratio of the area calculated
for oral administration compared withfor oral administration compared with
the area calculated for IV injectionthe area calculated for IV injection

13.  The key parameters for determiningThe key parameters for determining
bioavailabilitybioavailability
 1. AUC: The AUC is proportional to the1. AUC: The AUC is proportional to the
total amount of drug reaching thetotal amount of drug reaching the
systemic circulation, and thussystemic circulation, and thus
characterizes the extent of absorption.characterizes the extent of absorption.
 2. Cmax: Gives indication whether drug2. Cmax: Gives indication whether drug
is sufficiently absorbed systemically tois sufficiently absorbed systemically to
provide a therapeutic response.provide a therapeutic response.
 3. Tmax: The Tmax reflects the rate of3. Tmax: The Tmax reflects the rate of
drug absorption, and decreases as thedrug 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 theFirst-pass hepatic metabolism: When a drug is absorbed across the
GI tract, it enters the portal circulation before entering the systemicGI tract, it enters the portal circulation before entering the systemic
circulation (see Figure 1.3). If the drug is rapidly metabolized by thecirculation (see Figure 1.3). If the drug is rapidly metabolized by the
liver, the amount of unchanged drug that gains access to theliver, the amount of unchanged drug that gains access to the
systemic circulation is decreased. Many drugs, such as propranololsystemic circulation is decreased. Many drugs, such as propranolol
or lidocaine, undergo significant biotransformation during a singleor lidocaine, undergo significant biotransformation during a single
passage through the liver.passage through the liver.
 Solubility of the drug: Very hydrophilic drugs are poorly absorbedSolubility 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 poorlyParadoxically, drugs that are extremely hydrophobic are also poorly
absorbed, because they are totally insoluble in aqueous body fluidsabsorbed, because they are totally insoluble in aqueous body fluids
and, therefore, cannot gain access to the surface of cells. For aand, therefore, cannot gain access to the surface of cells. For a
drug to be readily absorbed, it must be largely hydrophobic, yetdrug to be readily absorbed, it must be largely hydrophobic, yet
have some solubility in aqueous solutions. This is one reason whyhave some solubility in aqueous solutions. This is one reason why
many drugs are weak acids or weak bases. There are some drugsmany drugs are weak acids or weak bases. There are some drugs
that are highly lipid-soluble, and they are transported in thethat 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 unstableChemical instability: Some drugs, such as penicillin G, are unstable
in the pH of the gastric contents. Others, such as insulin, arein 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 byNature of the drug formulation: Drug absorption may be altered by
factors unrelated to the chemistry of the drug. For example, particlefactors unrelated to the chemistry of the drug. For example, particle
size, salt form, crystal polymorphism, enteric coatings and thesize, salt form, crystal polymorphism, enteric coatings and the
presence of excipients (such as binders and dispersing agents) canpresence of excipients (such as binders and dispersing agents) can
influence the ease of dissolution and, therefore, alter the rate ofinfluence the ease of dissolution and, therefore, alter the rate of
absorption.absorption.

15. FACTORS INFLUENCING
BIOAVAILABILITY:
 Three distinct factors are involvedThree 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 thePhysicochemical properties of the
drug.drug.
 1. Particle size1. Particle size
 2. Crystalline structure2. Crystalline structure
 3. Salt form3. Salt form
Formulation and manufacturing
variables.
 1.Disintegration and dissolution time1.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 fluids1.Variations in pH of GI fluids
 2.Gastric emptying rate2.Gastric emptying rate
 3. Intestinal motility3. Intestinal motility
 4. Presystemic and first-pass metabolism4. Presystemic and first-pass metabolism
 5. Age, sex5. Age, sex
 6. Disease states6. Disease states
 Interactions with other
substances.
 1. Food1. Food
 2. Fluid volume2. Fluid volume
 3. Other drugs3. Other drugs

18. 3. Route of administration:3. Route of administration:
1.Parentral administration1.Parentral administration
2.Oral administration2.Oral administration
3.Rectal administration3.Rectal administration
4.Topical administration4.Topical administration

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

20. BioequivalenceBioequivalence
0
10
20
30
40
50
60
70
80
90
0 5 10 15 20 25 30
Time (hours)
Concentration(ng/mL)
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. PharmaceuticalPharmaceutical
EquivalentsEquivalents
Drug products are consideredDrug products are considered
pharmaceutical equivalents if theypharmaceutical equivalents if they
contain the same active ingredient(s),contain the same active ingredient(s),
have the same dosage form and route ofhave the same dosage form and route of
administration, and are identical inadministration, and are identical in
strength or concentrationstrength or concentration
 Equivalent products contain the sameEquivalent products contain the same
amount of ingredient in the same dosageamount of ingredient in the same dosage
form but may differ in characteristics,form but may differ in characteristics,
such as shape, release mechanisms, andsuch as shape, release mechanisms, and
packagingpackaging

23. PharmaceuticalPharmaceutical
AlternativesAlternatives
 Drug products are considered pharmaceuticalDrug products are considered pharmaceutical
alternatives if they contain the samealternatives if they contain the same
therapeutic moiety, are different salts, esters,therapeutic moiety, are different salts, esters,
or complexes of the same moiety, areor complexes of the same moiety, are
different dosage forms, or are differentdifferent dosage forms, or are different
strengthsstrengths
 Other pharmaceutical alternativesOther pharmaceutical alternatives
 Different dosage forms and strengths within aDifferent dosage forms and strengths within a
single product line by a single manufacturersingle product line by a single manufacturer
 Extended-release formulations whenExtended-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

27. Narrow therapeutic index:Narrow therapeutic index:
 having little difference between toxic andhaving little difference between toxic and
therapeutic dosestherapeutic doses
Large therapeutic index:Large therapeutic index:
 A high therapeutic index is preferable to a lowA high therapeutic index is preferable to a low
one: this corresponds to a situation in whichone: this corresponds to a situation in which
one would have to take a much higher amountone would have to take a much higher amount
of a drug to do harm than the amount taken toof 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 measuringThe therapeutic index is determined by measuring
the frequency of desired response, and toxicthe 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 andthe doses that produce the therapeutic effect and
the toxic effect in fifty percent of the population arethe 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 isIn humans, the therapeutic index of a drug is
determined using drug trials and accumulateddetermined using drug trials and accumulated
clinical experience. These usually reveal a range ofclinical experience. These usually reveal a range of
effective doses and a different (sometimeseffective doses and a different (sometimes
overlapping) range of toxic doses.overlapping) range of toxic doses.

29.  Although some drugs have narrowAlthough some drugs have narrow
therapeutic indices, they are routinelytherapeutic indices, they are routinely
used to treat certain diseases.used to treat certain diseases.
 Several lethal diseases, such asSeveral lethal diseases, such as
Hodgkin's lymphoma, are treated withHodgkin's lymphoma, are treated with
narrow therapeutic index drugs; however,narrow therapeutic index drugs; however,
treatment of a simple headache, fortreatment of a simple headache, for
example, with a narrow therapeutic indexexample, 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 narrowan oral anti-coagulant with a narrow
therapeutic index, and penicillin, antherapeutic index, and penicillin, an
antimicrobial drug with a large therapeuticantimicrobial 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, aAs the dose of warfarin is increased, a
greater fraction of the patients respondgreater 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, aHowever, at higher doses of warfarin, a
toxic response occurs, namely a hightoxic response occurs, namely a high
degree of anticoagulation that results indegree of anticoagulation that results in
hemorrhage.hemorrhage.
 When the therapeutic index is low, it isWhen the therapeutic index is low, it is
possible to have a range ofpossible to have a range of
concentrations where the effective andconcentrations 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 desiredwhereas others achieve the desired
two-fold prolongation of prothrombintwo-fold prolongation of prothrombin
time.time.
 Variation in patient response is,Variation in patient response is,
therefore, most likely to occur with atherefore, most likely to occur with a
drug showing a narrow therapeuticdrug showing a narrow therapeutic
index, because the effective and toxicindex, 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 criticallythat is, drugs for which dose is critically
important—are those drugs for whichimportant—are those drugs for which
bioavailability critically alters thebioavailability critically alters the

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

35. MARIYAM ATHERMARIYAM ATHER
CONCLUSION

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

37. BIOEQUIVALENCE
 Two related drugs are bioequivalentTwo related drugs are bioequivalent
if they show comparableif they show comparable
bioavailability and similar times tobioavailability and similar times to
achieve peak blood concentrations.achieve peak blood concentrations.
 Two related drugs with a significantTwo related drugs with a significant
difference in bioavailability are saiddifference 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.