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1st M.Pharm
Dept. of Pharmaceutics



❖ Drug product performance, in vivo, may be defined as the release
of the drug substance from the drug product leading to
bioavailability of the drug substance.

❖ Bioavailability and Bioequivalence studies can be considered as
measures of the drug product performance in vivo.

❖ The assessment of drug product performance is important since
bioavailability is related both to the pharmacodynamic response
and to adverse events. Thus, performance tests relate the quality
of a drug product to clinical safety and efficacy.

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✓ The effect of changes in the physicochemical properties of the
drug substance.

✓ The formulation of the drug and the manufacture process of
the drug product (dosage form).

✓ Drug product performance studies are used in the development
of new and generic drug products.

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❖ Bioavailability is defined as 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.

❖ Bioavailability is one aspect of drug product quality that links the in vivo
performance of a new drug product to the original formulation that was
used in clinical safety and efficacy studies.


❖ Bioequivalence is defined as the absence of a significant difference in the
rate and extent to which the active ingredient or active moiety becomes
available at the site of drug action when administered at the same molar
dose under similar conditions in an appropriately designed study.

❖ Bioequivalence studies are drug product performance tests that compare the
bioavailability of the same active pharmaceutical ingredient from one drug
product (test) to a second drug product (reference).

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Bioequivalence Studies in New Drug Development

✓ During drug development, bioequivalence studies are used to

(a) early and late clinical trial formulations.
(b) formulations used in clinical trials and stability studies,

if different.
(c) clinical trial formulations and to-be-marketed drug

products, if different.
(d) product strength equivalence, as appropriate.

Bioequivalence study designs are used to support new
formulations of previously approved products.

✓ Bioequivalence studies may be needed to support regulatory
approval of major changes in formulation, manufacturing, or
site, in comparison to reference formulation.

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✓ The marketed drug product that is approved by the US Food and Drug
Administration (FDA) may not be the same formulation that was used in the
original safety and clinical efficacy studies.

✓ After the drug product is approved by the FDA and marketed, the
manufacturer may perform changes to the formulation.

✓ These postapproval changes, often termed SUPAC (scale-up and
postapproval change based on several FDA guidance documents).

✓ In each case, the manufacturer must demonstrate that drug product
performance did not change and is the same for the drug product
manufactured before and after the SUPAC change.

✓ Drug product performance may be determined by in vivo bioequivalence
studies or by in vitro comparative drug release or dissolution profiles.

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Fig : Drug product performance and new drug product development for NDAs

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Bioequivalence Studies in Generic Drug Development

✓ Clinical safety and efficacy studies are not generally performed on generic
drug products.

✓ Since the formulation and method of manufacture of a drug product can
affect the bioavailability and stability of the drug, the generic drug
manufacturer must demonstrate that the generic drug product is
pharmaceutically equivalent, bioequivalent, and therapeutically equivalent to
the comparator brand-name drug product.

✓ Drug product performance comparison for oral generic drug products is
usually measured by in vivo bioequivalence studies in normal healthy adult
subjects under fasted and fed conditions.

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✓ Similar to the brand-name drug product manufacturer, the generic drug
manufacturer may make changes after FDA approval in the formulation,
in the source of the active pharmaceutical ingredient, manufacturing
process, or other changes.

✓ For any postapproval change, the manufacturer must demonstrate that the
change did not alter the performance of the drug product.

Fig: Drug product performance and generic drug product development.
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✓ Bioavailability studies are important in the process of approving
pharmaceutical products for marketing.

✓ Bioavailability data provide an estimate of the fraction of drug absorbed from
the formulation, and provide information about the pharmacokinetics of the

✓ Bioavailability data play pivotal roles in regulatory submissions for marketing
approval of new drugs throughout the world.

✓ Each regulatory agency has developed its own unique system of guidelines
advising new drug applicants on how to conduct acceptable bioavailability
studies to support marketing approval.

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➢ Regulatory agencies such as the FDA require submission of
bioavailability data in applications to market new drug products.

➢ A drug product’s bioavailability provides an estimate of the
relative fraction of the administered dose that is absorbed into
the systemic circulation. (USFDA)

➢ Determining the fraction (f) of administered dose absorbed
involves comparing the drug product’s systemic exposure
(represented by the concentration-versus-time or
pharmacokinetic profile) with that of a suitable reference

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✓ For systemically available drug products, bioavailability is most
often assessed by determining the area under the drug plasma
concentration-versus-time profile (AUC).

✓ The AUC is considered the most reliable measure of a drug’s

bioavailability, as it is directly proportional to the total amount
of unchanged drug that reaches the systemic circulation.

✓ The drug concentration-versus-time profile is used to identify
the pharmacokinetic parameters that form the basis of
bioavailability and bioequivalence comparisons.

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Fig 1: Plasma drug concentration–time curve after oral drug administration

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Absolute Bioavailability

✓ Absolute bioavailability compares the bioavailability of the
active drug in the systemic circulation following extravascular
administration with the bioavailability of the same drug
following intravenous administration.

✓ Intravenous drug administration is considered 100% absorbed.

✓ The route of extravascular administration can be inhaled,
intramuscular, oral, rectal, subcutaneous, sublingual, topical,
transdermal, etc.

✓ The absolute bioavailability is the dose-corrected AUC of the
extravascularly administered drug product divided by the AUC
of the drug product given intravenously.

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✓ For an oral formulation, the absolute bioavailability is
calculated as follows:

Fabs = AUCpo . Div

AUCiv . Dpo

▪ Fabs is the fraction of the dose absorbed, expressed as a


▪ AUCpo is the AUC following oral administration.

▪ Div is the dose administered intravenously.

▪ AUCiv is the AUC following intravenous administration.

▪ Dpo is the dose administered orally.

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✓ Absolute availability, Fabs, may be expressed as a fraction or as
a percent by multiplying Fabs × 100.

✓ A drug given by the intravenous route will have an absolute
bioavailability of 100% (f = 1).

✓ A drug given by an extravascular route may have an
Fabs = 0 (no systemic absorption) and
Fabs = 1.0 (100% systemic absorption).

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Fig 2 : Relationship between plasma drug concentration-versus-time profiles for an
intravenously administered formulation versus an orally administered formulation.
In an absolute bioavailability study, the systemic exposure profile of a drug
administered by the oral route (black curve) is compared with that of the drug
administered by the intravenous route (green curve).

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Relative Bioavailability

✓ Relative bioavailability is another type of comparative
bioavailability assessment.

✓ In a relative bioavailability study, the systemic exposure of a
drug in a designated formulation (generally referred to as
treatment A or reference formulation) is compared with that of
the same drug administered in a reference formulation (generally
referred to as treatment B or test formulation).

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✓ In a relative bioavailability study, the AUCs of the two
formulations are compared as follows:

Frel = 100. AUCA . DB


▪ Frel is the relative bioavailability of treatment A (formulation),

expressed as a percentage.

▪ AUCA is the AUC following administration of treatment A

▪ DA is the dose of formulation A.

▪ AUCB is the AUC of formulation B.

▪ DB is the dose of formulation B.

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✓ Relative bioavailability studies are frequently included in regulatory
submissions. For example, the FDA recommends that new drug developers
routinely use an oral solution as the reference for a new oral formulation, for
the purpose of assessing how formulation impacts bioavailability.

✓ Relative bioavailability studies used in drug development include studies to
characterize food effects and drug–drug interactions. In a food-effect
bioavailability study, oral bioavailability of the drug product given with food
(usually a high-fat, high-calorie meal) is compared to oral bioavailability of
the drug product given under fasting conditions.

✓ Relative bioavailability studies are used in developing new formulations of
existing immediate-release drug products, such as new modified-release
versions or new fixed-dose combination formulations.

✓ Relative bioavailability study designs are also commonly used for bridging
formulations during drug development.

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✓ Direct and indirect methods may be used to assess drug bioavailability.

✓ For drug products that are not intended to be absorbed into the bloodstream,
bioavailability may be assessed by measurements intended to reflect the rate
and extent to which the active ingredient or active moiety becomes available
at the site of action.

✓ The design of the bioavailability study depends on :

▪ the objectives of the study
▪ the ability to analyze the drug (and metabolites) in

biological fluids.
▪ the pharmacodynamics of the drug substance.
▪ the route of drug administration.
▪ the nature of the drug product.

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✓ For all systemically active drugs, with a few exceptions,
bioequivalence should be demonstrated by an in vivo study
based on pharmacokinetic (PK) endpoints, as this is the most
sensitive, accurate, and reproducible approach.

✓ The other approaches—PD, clinical, or in vitro—may be more
appropriate for locally acting drugs that are not systemically

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Pharmacokinetic Approach

➢ Plasma drug concentration

1. Time for peak plasma (blood) concentration (tmax)
2. Peak plasma drug concentration (Cmax)
3. Area under the plasma drug concentration–time curve


➢ Urinary drug excretion

1. Cumulative amount of drug excreted in the urine (Du)
2. Rate of drug excretion in the urine (dDu/dt)
3. Time for maximum urinary excretion (t)

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Plasma Drug Concentration


✓ The time of peak plasma concentration, tmax, corresponds to the time
required to reach maximum drug concentration after drug administration.

✓ At tmax, peak drug absorption occurs and the rate of drug absorption
exactly equals the rate of drug elimination.

✓ Drug absorption still continues after tmax is reached, but at a slower rate.

✓ When comparing drug products, tmax can be used as an approximate
indication of drug absorption rate.

✓ The value for tmax will become smaller (indicating less time required to
reach peak plasma concentration) as the absorption rate for the drug
becomes more rapid.

✓ Units for tmax are units of time (eg. hours, minutes).
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✓ The peak plasma drug concentration, Cmax, represents the maximum
plasma drug concentration obtained after oral administration of drug.

✓ The units of Cmax are concentration units (eg. mg/mL, ng/mL).

✓ Cmax provides indications that the drug is sufficiently systemically
absorbed to provide a therapeutic response.

✓ Cmax provides warning of possibly toxic levels of drug.

✓ Cmax is often used in bioequivalence studies as a surrogate measure for
the rate of drug bioavailability.

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✓ The area under the plasma level–time curve, AUC, is a measurement of the
extent of drug bioavailability.

✓ The AUC reflects the total amount of active drug that reaches the systemic

✓ The AUC is the area under the drug plasma level–time curve from t = 0 to t =
∞, and is equal to the amount of unchanged drug reaching the general
circulation divided by the clearance.

F = fraction of dose absorbed, D0 = dose, k = elimination rate constant, and
VD = volume of distribution.

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✓ For many drugs, the AUC is directly proportional to dose. For
example, if a single dose of a drug is increased from 250 to
1000 mg, the AUC will also show a fourfold increase.

✓ In some cases, the AUC is not directly proportional to the
administered dose for all dosage levels. For example, as the
dosage of drug is increased, one of the pathways for drug
elimination may become saturated.

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Fig 3 : Plasma concentration versus Time

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Urinary Drug Excretion Data

✓ Urinary drug excretion data is an indirect method for
estimating bioavailability.

✓ The drug must be excreted in significant quantities as
unchanged drug in the urine.

✓ In addition, timely urine samples must be collected and the
total amount of urinary drug excretion must be obtained.

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Cumulative amount of drug excreted in the urine (Du) :

✓ The cumulative amount of drug excreted in the urine.

✓ Du, is related directly to the total amount of drug absorbed.

✓ Experimentally, urine samples are collected periodically after
administration of a drug product.

✓ Each urine specimen is analyzed for free drug using a specific

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✓ The relationship between the cumulative amount of drug excreted in the urine
and the plasma level– time curve is shown in the graph.

Fig 4: Corresponding plots relating the plasma level–time curve and the
cumulative urinary drug excretion.

✓ When the drug is almost completely eliminated (point C), the plasma
concentration approaches zero and the maximum amount of drug excreted in
the urine, Du, is obtained.

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The rate of drug excretion (dDu/dt)

✓ Because most drugs are eliminated by a first-order rate
process, the rate of drug excretion is dependent on the first-
order elimination rate constant, k, and the concentration of
drug in the plasma, Cp.

✓ The maximum rate of drug excretion, (dDu/dt)max, is at point
B, whereas the minimum rate of drug excretion is at points A
and C. (Fig 5)

✓ Thus, a graph comparing the rate of drug excretion with
respect to time should be similar in shape to the plasma level–
time curve for that drug. (Fig 6)

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Fig 5 : Corresponding plots relating the plasma level–time curve and the
cumulative urinary drug excretion.

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Fig 6 : Corresponding plots relating the plasma level–time curve and the rate
of urinary drug excretion.

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The total time for the drug to be excreted (t∞):

✓ In Figs. 5 & 6, the slope of the curve segment A–B is related
to the rate of drug absorption, whereas point C is related to
the total time required after drug administration for the drug
to be absorbed and completely excreted, t = ∞.

✓ The t∞ is a useful parameter in bioequivalence studies that
compare several drug products.

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Reference :

✓ Applied Biopharmaceutics & Pharmacokinetics, Seventh
Edition, By Leon Shargel & Andrew B.C. Yu. (Page no.

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