Bioavailability

&
Bioequivalence
• Physiologic availability, biologic availability or
simply bioavailability:
✎ is the ability of the dosage form to deliver
the medicament to its site of action at a rate
and amount sufficient to elicit the desired
pharmacologic response.
• Bioavailable fraction F = the fraction of dose
that enters the systemic circulation.
 ✎Factors affecting bioavailability
• Factors affecting bioavailability may be classified into two general
categories:
• ☺Formulation factors will include, but are not limited to:
1. excipients (type and concentration).
2. particle size of API.
3. crystalline or amorphous nature of the drug.
4. hydrous or anhydrous form of the drug.
5. polymorphic nature of a drug.
• ☺Physiological factors will include, among others:
1. gastric emptying.
2. intestinal motility.
3. changes in gastrointestinal pH.
4. changes in nature of intestinal wall.
The first-pass effect (presystemic clearance)
• The fraction, f, of orally administered drug that
successfully passes through gut lumen and gut
wall is then taken via the hepatic portal vein to
the liver, where metabolism of the drug by
enzymes may take place.
• The fraction of drug entering the liver that
survives the first-pass effect is designated by the
notation (F*). Where (F*) must equal (1— E),
where E is the hepatic extraction ratio.
• The passage of drug molecules from the
gastrointestinal tract to the general
circulation and some factors that will play
a role, following oral administration, are
shown in the figure below
• The overall extent of bioavailability is the product of two
factors reflecting: traversing the gastrointestinal membrane
and, surviving the first-pass effect in the liver.
• See the equation below:
F=fF*
• Where:
 F = the fraction of administered drug that eventually
reaches the general circulation.
 f = the fraction of dose absorbed from gut into the portal
circulation.
 F* = the fraction of absorbed dose that survives the first
pass effect.
• Example
• If the fraction absorbed into the portal circulation is
0.9, and the fraction that survives the first pass effect
is 0.7 from a 500mg dose of drug A.
• What is the percentage of drug A that eventually
reaches the general circulation?
• If the AUCiv of drug A after 250mg is 32, what is the
AUC for the above oral dose?
• If drug A is partially eliminated through other routes
of elimination and that only 225mg of the above iv
dose is excreted unchanged in urine, what is the
amount from the oral dose that is excreted
unchanged in urine?
 Objectives of Bioavailability Studies
• Bioavailability studies are important in the:
1. Primary stages of development of a dosage form
for a new drug entity.
2. Determination of influence of excipients, patient
related factors and possible interaction with
other drugs on the efficiency of absorption.
3. Development of new formulations of the
existing drugs.
4. Control of quality of a drug product during the
early stages of marketing in order ,to determine
the influence of processing factors, storage and
stability on drug absorption.
• Bioavailability-Absolute versus Relative
• When the systemic availability of a drug
administered orally is determined in
comparison to its intravenous administration,
it is called absolute bioavailability and
denoted by F.
• Intravenous dose is selected as a standard
because the drug is 100% bioavailable and
there is no absorption step.
• Intramuscular dose can also be taken as a
standard if the drug is poorly water soluble.
• An oral solution as reference standard has
also been used in certain cases.
• When we use oral solution as a standard
instead of an i. v. dose, there are several
drawbacks including:
1. Limits the pharmacokinetic treatment to one-
compartment model only
2. Differentiation between the fraction of dose
unabsorbed and that metabolized is difficult.
3. If the rate of absorption is not sufficiently
greater than the rate of elimination, the true
elimination rate constant cannot be computed.
• But, when oral solution is used in conjunction
with i.v. route, one can distinguish the
dissolution rate limitation in drug absorption
from solid dosage forms.
• When the systemic availability of a drug after
oral administration is compared with that of
an oral standard of the same drug (such as an
aqueous or non-aqueous solution or a
suspension), it is referred to as relative
bioavailability and denoted by symbol Fr.
• In contrast to absolute bioavailability, it is
used to characterize absorption of a drug from
its formulation.
 F and Fr are generally expressed in
percentages.
Single Dose versus Multiple Dose Studies
• Single dose bioavailability studies are very
common.
• They are: easy, offer less exposure to drugs and
are less tedious.
• However, it is difficult to predict the steady state
characteristics of a drug and intersubject
variability with such studies.
• On the Other hand, multiple dose study is :
difficult to control (poor subject compliance),
exposes the subject to more drug and is highly
tedious and time consuming.
• Nevertheless, multiple dose study has several
advantages:
1. More accurately reflects the manner in which the
drug should be used.
2. Easy to predict the peak and valley characteristics of
the drug since the bioavailability is determined at
steady-state.
3. Requires collection of fewer blood samples.
4. The drug blood levels are higher due to cumulative
effect which makes its determination possible even
by the less sensitive analytic methods.
5. Can be ethically performed in patients
because of the therapeutic benefit to the
patient.
6. Intersubject variability is observed in such a
study.
7. Better evaluation of the performance of a
controlled release formulation is possible.
8. Nonlinearity in pharmacokinetics, if present,
can be easily detected.
☹Human Volunteers-Healthy Subjects
versus Patients
• Ideally☑, the bioavailability study should be
carried out in patients for whom the drug is
intended to be used because of the following
advantages:
1. The patient will be benefited from the study.
2. Reflects the therapeutic efficacy of a drug.
3. Drug absorption pattern in disease states can be
evaluated.
4. Avoids the ethical quandary of administering
drugs to healthy subjects
• But, the drawbacks of using patients as volunteers are
equally large:
a. disease.
b. other drugs.
c. physiologic changes.
d. difficulty of applying stringent study conditions
required.
• Such studies are therefore usually performed in young
(20 to 40 years), healthy, male adult volunteers (body
weight within a narrow range;±10%) under restricted
dietary and fixed activity conditions. Female volunteers
are used only when drugs such as oral contraceptives
are to be tested.
• The following should be considered:
1. The consent of volunteers must be obtained and they
must be informed about the importance of the study,
conditions to be followed during the study and
possible hazards if any.
2. Medical examination should be performed. in order
to exclude subjects with any kind of abnormality or
disease.
3. The volunteers must be instructed to abstain from any
medication for at least a week and to fast overnight
prior to ,and for a minimum of 4 hours after dosing.
4. The volume and type of fluid and the standard diet to
be taken must also be specified.
5. Drug washout period for a minimum of ten biological
half-lives must be allowed for between any two
studies in the - same subject.
 Measurement of Bioavailability
• The methods useful in quantitative evaluation of
bioavailability can be broadly divided into two
categories: pharmacokinetic methods and
pharmacodynamic methods.

I. Pharmacokinetic Methods
• These are indirect methods, based on the assumption
that the pharmacokinetic profile reflects the
therapeutic effectiveness of a drug.
• The two major pharmacokinetic methods are:
1) Plasma level-time studies.
2) Urinary excretion studies.
• II. Pharmacodynamic Methods
• These methods are complementary to
pharmacokinetic approaches and involve direct
measurement of drug effect on a
(patho)physiologic process as a function of time.
• The two pharmacodynamic methods involve
determination of bioavailability from:
1) Acute pharmacologic response.
2) Therapeutic response.
Plasma Level-Time Studies
• If possible, it is the most reliable method and
method of choice in comparison to urine data.
• The method is based on the assumption that
two dosage forms that exhibit superimposable
plasma level-time profiles in a group of
subjects should result in identical therapeutic
activity.
• With single dose study, serial blood samples are
collected for a period of 2 to 3 biological half-lives
after drug administration, analysed for drug
concentration and the concentration is plotted
versus corresponding time of sample collection to
obtain the plasma level time profile.
• With iv dose, sampling should start within 5
minutes of drug administration and subsequent
samples taken at 15 minute intervals.
• For oral dose at least 3 points should be taken on
the ascending part of the curve for accurate
determination of Ka.
• The 3 parameters of plasma level-time studies
which are considered important for determining
bioavailability are:
1. Cmax: The peak plasma concentration that
gives an indication whether the drug is
sufficiently absorbed systemically to provide
a therapeutic response.
2. tmax: The ,peak time that gives an indication
of the rate of absorption.
3. AUC: The area under the plasma level-time
curve that gives a measure of the extent of
absorption.
• The extent of bioavailability can be determined by
following equations:

• See below for the determination of AUC and Cssmax

on multiple dosing up to steady-state
• With multiple dose study, the drug is administered
for at least 5 biological half-lives (i.e. at least 5 doses)
to reach the steady state.
• A blood sample should be taken at the end of previous dosing
interval and 8 to 10 samples after the administration of next
dose.
Determination of the area under the plasma
concentration—time curve from iv bolus dose
• The following equation is applied for the one-
compartment model when the drug is
intravenously administered.
• Cpt=(X0 /V) e-kt
• Where:
• Cpt is plasma concentration at time t;
• X0 is the administered dose;
• V is the apparent volume of distribution;
• K is the first-order elimination rate constant.
We also know that:
• Recognizing that Xo is the administered dose and
VK is the systemic clearance (Cl)s, as seen in the
equation below, which shows that (AUC) is
directly proportional to the administered dose
Determination of the area under the plasma
concentration—time curve from extra-vascular route of
drug administration
• For a drug administered by an extra-vascular route the
equation below is applied which is then integrated to obtain
the AUC.
• Where FX0 is the fraction of drug absorbed
into the systemic circulation multiplied by the
administered dose (i.e. the amount of drug
available to reach the general circulation);
• VK is the systemic clearance.
• If the drug under consideration undergoes
metabolism or the first-pass effect, then
F=fF*
• The integrated equation above can be simplified
as follows:
• If we take the ratio of AUC for an extra-
vascular route to that for an intravenous
solution.
• Figure 7.8
Determination of the extent of
absorption (AUC)
• One can also determine the extent of
absorption [i.e. AUC ] for an
extravascularly administered dose of a drug
by following the trapezoidal rule, where the
AUC is calculated as the sum of the areas of
trapezoids plus and area of the tail as
shown below
Assessing the rate of absorption
• The rate of absorption is assessed by comparing the
following two parameters:
1. peak time (tmax).
2. peak plasma concentration (Cp)max.
• The figure below shows assessment of the rate and
extent of the drug absorption from two different
formulations (A and B) of the same drug.
• NB:
• Cs, serum concentration;
• MTC, minimum toxic concentration;
• MEC, minimum effective concentration.
• Example:
In a study to evaluate the bioavailability of an
antibiotic, a patient received single 250-mg IV
bolus dose, a single 500-mg oral suspension
dose and single 500-mg oral capsule dose, on
three separate occasions and the following
plasma concentrations were obtained:
• The half-life of this antibiotic is 3hr, and the absorption
process is complete after 12hr of oral administration,
• 1. Calculate the absolute bioavailability of the oral
suspension and capsule
• 2. Calculate the bioavailability of the oral capsule relative
to the oral suspension.
• NB:
• the CP0 for IV dose = 8mg/L.
• And the area of the tail is obtained as: Clast/K or 1.44 Clast t½
• AUC for IV dose =c p0/K.
• AUCs for capsule are calculated using linear trapezoidal
rule.
• In calculating absolute bioavailability remember that the IV
and oral doses are not equal i.e. (F = AUCoral X Div/AUC X
Doral).
 Urinary Excretion Studies
• This method is based on the principle that the urinary
excretion of unchanged drug is directly proportional to
the plasma concentration of drug.
• The study is particularly useful for drugs extensively
excreted unchanged in the urine - for example, certain
thiazide diuretics and sulfonamides and for drugs that
have urine as the site of action - for example, urinary
antiseptics such as nitrofurantoin and hexamine.
• Concentration of metabolites excreted in urine is never
taken into account in calculations since a drug may
undergo presystemic metabolism
• The method involves collection of urine at
regular intervals for a time span equal to 7
biological half-lives, analysis of unchanged
drug in the collected sample and
determination of the amount of drug
excreted in each interval and cumulative
amount excreted.
• Total emptying of the bladder and frequent
sampling are essential in order to compute
correctly
• The three major parameters examined in urinary excretion
data obtained with a single dose study are:
• (dXu/dt)max : The maximum urinary excretion rate, it is
obtained from the peak of plot between rate of excretion
versus midpoint time of urine collection period.
• It is analogous to the Cmax since the rate of appearance of
drug in the urine is proportional to its concentration in
systemic circulation.
• (tu)max: The time for maximum excretion rate, it is analogous to
the tmax.
• Xu: The cumulative amount of drug excreted in the urine, it is
related to the AUC of plasma level data and increases as the
extent of absorption increases.
See below for plot of excretion rate versus time.
• The extent of bioavailability is calculated
from equations given below:
• With multiple dose study to steady-state, the
equation for computing bioavailability is:

• Where (Xu,ss) is the amount of drug excreted

unchanged during a single dosing interval at steady-
state.
A cute Pharmacologic
Response
• When the bioavailability measurement by
pharmacokinetic methods is difficult or
inaccurate, an acute pharmacologic effect
such as change in ECG or EEG readings, pupil
diameter, etc. is related to the time course of
a given drug.
• Bioavailability can then be determined by
construction of pharmacologic effect-time
curve as well as dose-response graphs.
• The method requires measurement of responses for
at least 3 biological half-lives of the drug in order to
obtain a good estimate of AUC.
• A disadvantage of this method is that the
pharmacologic response tends to be more variable
and accurate correlation between measured
response and drug available from the formulation is
difficult.
• Moreover, the observed response may be due to an
active metabolite whose concentration is not
proportional to the concentration of parent drug.
Therapeutic Response
• This method is based on observing the clinical
response to drug formulation given to patients
suffering from disease for which it is intended
to be used.
• A major drawback of this method is that
quantitation of observed response is too
improper to allow for reasonable assessment of
relative bioavailability between two dosage
forms of the same drug.
Drug Dissolution Rate and Bioavailability
• The best way to assess therapeutic efficacy of drugs
with slow dissolution rate is in vivo determination of
bioavailability which is usually done whenever a new
formulation is to be marketed.
• However, monitoring batch-to-batch consistency
through use of such a method is extremely costly,
tedious and time consuming besides exposing the
healthy subjects to hazards of drugs. It would
therefore be always desirable to substitute it with
inexpensive in Vitro methods like, the vitro
dissolution test.
 In Vitro Dissolution Testing
Models
• Despite the efforts to mimic the
environment offered by the biological
system, the in vitro dissolution technique is
still by no means a perfect approach.
 Factors that to be considered in the design of
a dissolution test
1. Factors related to the dissolution apparatus such as:
the design, the size of the container, the shape of the
container (round bottomed or flat), nature of agitation
(stirring, rotating or oscillating methods), speed of agitation,
performance of the apparatus, etc.
2. Factors related to the dissolution fluid such as:
composition (water, 0.1 N HCI, phosphate buffer, simulated
gastric fluid, simulated intestinal fluid, etc.), viscosity,
volume (generally larger than that needed to completely
dissolve the drug under test), temperature (generally 370C)
and maintenance of sink (drug concentration in solution
maintained constant at a low level) or nonsink conditions
(gradual increase in the drug concentration in the
dissolution medium).
3. Process parameters such as:
method of introduction of dosage form, sampling
techniques, changing the dissolution fluid, etc.

• The dissolution apparatus has evolved from a

simple beaker type to a highly versatile and fully
automated instrument. The devices can be
classified in a number of ways.
• Based on the absence or presence of sink conditions, there are two
principal types of dissolution apparatus:

1. Closed-compartment apparatus:
It is a limited-volume apparatus in which the dissolution fluid is restrained
to the size of the container, e.g. beaker type apparatus

2. Open-compartment apparatus:
It is the one in which the dosage form is contained in a column which is
brought in continuous contact with fresh flowing dissolution medium
(perfect sink condition).

3. A third type called dialysis systems:

are used for very poorly aqueous soluble drugs for which maintenance of
sink conditions would otherwise require large volume of dissolution fluid.

 But we shall discuss only the official methods.

Rotating Basket Apparatus (Apparatus 1)
• It is a beaker type apparatus comprising of a
cylindrical glass vessel with hemispherical bottom of
one liter capacity partially immersed in a water bath
to maintain the temperature at 370C.
• A cylindrical basket made of 22 mesh to hold the
dosage form is located centrally in the vessel, at a
distance of 2 cm from the bottom and rotated by a
variable speed motor through a shaft as seen below.
• The basket should remain in motion during drawing of
samples.
• All metal parts like basket and shaft are made of S.S.?
Rotating Paddle Apparatus (Apparatus 2)

• The assembly is same as that for apparatus I

except that the rotating basket is replaced with a
paddle which acts as a stirrer.
• The dosage form is allowed to sink to the bottom
of the vessel.
• A small, loose, wire helix may be attached to the
dosage form that would otherwise float.
 In Vitro-In Vivo Correlation
• A simple in vitro dissolution test will be insufficient to
predict the therapeutic efficacy.
• Convincing correlation between in vitro dissolution
behavior of a drug and it's in vivo bioavailability must be
experimentally demonstrated to guarantee
reproducibility of biologic response.
• The two major objectives of developing such a
correlation are:
1. To ensure batch-to-batch consistency in the physiologic
performance of a drug product by use of such in vitro
values.
2. To serve as a tool in the development of a new dosage
form with desired in vivo performance.
• ☞There are two basic approaches by which a
correlation between dissolution testing and
bioavailability can be developed:
1. By establishing a relationship, usually linear,
between the in vitro dissolution and the in vivo
bioavailability parameters, and
2. By using the data from previous bioavailability
studies to modify the dissolution methodology
in order to arrive at meaningful in vitro-in vivo
correlation.
 ☞Some of the often used quantitative linear
in vitro-in vivo correlations are:
1. Correlations Based on the Plasma Level Data:
Here linear relationships between dissolution parameters such as
percent drug dissolved, rate of dissolution, rate constant for
dissolution, etc. and parameters obtained from plasma level data such
as percent drug absorbed, rate of absorption, Cmax, tmax; Ka, etc. are
developed; for example, percent drug dissolved versus percent drug
absorbed plots.
2. Correlation Based on the Urinary Excretion Data:
Here, dissolution parameters are correlated to the amount of drug
excreted unchanged in the urine, cumulative amount of drug excreted
as a function of time, etc.
3. Correlation Based on the Pharmacologic Response:
An acute pharmacologic effect such as LD50 in animals is related to any
of the dissolution parameters.
 ❁❁
BIOEQUIVALENCE
STUDIES
❁❁
• Always, there are several formulations of the
same drug, in the same dose, in a similar dosage
form and meant to be given by the same route.
• Substitution of one product for another can be
made provided they are equally effective
therapeutically as the standard one.
• In order to ensure clinical performance of such
drug products, bioequivalence studies should be
performed.
 Following are definitions for some important terms
relevant in this context.
✿ Equivalence:
It is a relative term that compares drug products with
respect to a specific characteristic or function or to a
defined set of standards.
• There are several types of equivalences:
• 1. ☯Chemical Equivalence: It indicates that two or more
drug products contain the same labeled chemical
substance as an active ingredient in the same amount.

• 2. ☯Pharmaceutic Equivalence: This term implies that

two or more drug products are identical in strength,
quality, purity, .content uniformity and disintegration and
dissolution characteristics; they may however differ in
containing different excipients.
3. ☯Bioequivalence: It is a relative term which denotes
that the drug substance in two or more identical dosage
forms, reaches the systemic circulation at the same
relative rate and to the same relative extent i.e. their
plasma concentration-time profiles will be identical
without significant statistical differences.
When statistically significant differences are observed in
the bioavailability of two or more drug products,
bioinequivalence is indicated.
4. ☯Therapeutic Equivalence: This term indicates that
two or more drug products that contain the same
therapeutically active ingredient, elicit identical
pharmacologic effects and can control the disease to the
same extent.
• Pharmaceutical alternatives:
• Are drug products that contain the same
therapeutic moiety but differ in: salt or ester
form dosage form or strength.
• Also, controlled-release dosage forms are
pharmaceutical alternatives when compared
with conventional formulations of the same
active ingredients.
• NB: Pharmaceutical alternatives are not
interchangeable.
• Brand name:
This is a trade name that is privately owned by the
manufacturer or distributer and is used to distinguish a
certain product from the competitors'
• Chemical name:
Name used by the organic chemist to indicate the
chemical structure of the drug (eg, N-acetyl-p-
aminophenol)
• Drug product:
This is the finished dosage form (eg, tablet, capsule or
solution) that contains the active ingredient, generally,
but not necessarily in association with inactive
ingredients.
• Drug substance:
This is the active pharmaceutical ingredient (API)
• Generic name: ☤
The established, nonproprietary or common name
of the active drug in a drug product (e.g.,
Paracetamol).
• Generic substitution:
The process of dispensing a different brand or
unbranded drug product in place of the prescribed
drug product. The substituted drug product has the
same active as the same salt or ester in the same
dosage form but is made by a different
manufacturer.
• Pharmaceutical substitution
The process of dispensing a pharmaceutical
alternative for the prescribed drug product (e.g.,
amoxicillin suspension in place of amoxicillin
capsule or tetracycline hydrochloride in place of
tetracycline phosphate).
• Therapeutic alternatives
Drug products containing different actives that are
indicated for the same clinical objectives (e.g.,
ibuprofen in place of aspirin or cimetidine in place
of ranitidine).
• Therapeutic substitution
• The process of dispensing the therapeutic
alternative in place of the prescribed drug
product (e.g., amoxicillin in place of ampicillin
or paracetamol in place of aspirin).

• The in vivo bioequivalence study requires

determination of relative bioavailability after
administration of a single dose of test and
reference formulations by the same route, in
equal doses, but at different times.
• The reference product is generally a previously
approved product, usually the innovator's product or
some suitable reference standard.
• The study is performed in fasting, ,young; healthy,
adult male volunteers to assure homogeneity in the
population and to spare the patients, elderly or
pregnant women from rigors of such a clinical
investigation.
• Homogeneity in the study population permits focus on
formulation factors.
• The volunteers are used in a study design where the
same subjects receive both formulations (with a
washout period in between).
Statistical Interpretation of Bioequivalence
Data
• After the data has been collected, statistical
methods must be applied to determine the
level of significance of any observed difference
in the rate and/or extent of absorption in
order to establish bioequivalence
• Typically, an analysis of variance (ANOV A)
method is applied to determine statistical
differences.
• If a statistically significant difference is
observed, it is important to determine if it is
clinically significant.
• It is found that for e.g. a statistically significant
difference of 10% in the extent of absorption
between the two formulations is insignificant
clinically-
• Currently, a simple acceptable rule is that if the
relative bioavailability of the test formulation is in
the range 80 to 120% of reference standard, it is
considered bioequivalent.
• Another accepted opinion is that the difference
between the bioavailabilities of the test
formulations should not be greater than ±20% of
the average of reference standard.
Bioequivalency testing: an example

• Twelve subjects ( healthy volunteers) were

assigned at random to one of two groups, A or
B.
• The six subjects in group A received a single
oral dose (250 mg) of a generic formulation
(formulation 1) of a calcium channel blocker.
• Based on 10 plasma drug concentrations
determined from each subject, AUC values
were calculated.
• After waiting a suitable number of days (7 t½s) to
allow washout, these same six subjects were
given the same dose of the standard (brand
name) drug (formulation 2).
• Blood concentrations were again taken and a new
set of AUC values were calculated.
• The sequence of receiving the generic drug in the
first time period and the standard in the second
time period was labeled sequence A.
• Subjects in group A underwent sequence A.
• The six subjects in sequence group B received the
standard (formulation2) in period I and the
generic (formulation 1) in period II.
AUC values and their natural logarithm transformations are shown in the
table below:
• The mean (average) of all the AUCs resulting
from taking the generic (X-barl) was 31.60 (in
AUC units).
• The mean for the standard (X-bar2) was 34.79.
• The ratio (X-bar1)/(X-bar2) was 0.9083.
• That is, the generic was within 10% of the
standard mean.
• Is that good enough for bioequivalence?
Use of the confidence interval
• The current bioequivalence rule is not to use the
ratio of means, as above, but instead to use the
90% confidence interval around the ratio of
medians-
• When this confidence interval is calculated, it
must fall within 80—125% of the standard or the
products are considered to lack bioequivalence.
• So, what is a confidence interval and how do you
calculate it?
• If an AUC is chosen at random from a subject who
received the generic drug formulation, then another
AUC is chosen at random from a subject who
received the standard drug formulation, and if the
ratio AUC generic/AUC standard was then calculated,
it would be highly unusual to exactly hit the mean or
median value determined by using all the AUC
generic/AUC standard ratios.
• However, there must be a range of ratios within
which the calculated ratio has a 90% chance of
fitting, and an even wider range of ratios that the
ratio has a 95% chance of being within, (only a 5%
chance of being outside).
• The "90% chance" range is the 90% confidence
interval; while the wider "95% chance" range is
the 95% confidence interval
• The 90% confidence interval for the ratio of
medians is:
• Where XLTI is the average of the lnAUC
values of the generic; XLT2 is the average of
the lnAUC values of the standard; (t) is
obtained from a statistical table (it equals
1.812 for a 90% confidence interval for
this 12 subject crossover experiment); and
SE is the standard error from an analysis
of variance of the ln transformed data.
• For these data, the analysis of variance produced SE 0.0633,
XLT1 =3.4025, and XLT2 = 3.4967.
• Therefore,:
exp(XLT1 - XLT2 – (t)(SE)) = e-0.20887 = 0.8115.
and exp(XLT1-XLT2 +(t)(SE)) = e+0.02053 = 1.0207.
• Does this confidence interval fall within the FDA limits of
0.80—1.25 (80—125%)?
• The answer is "Yes" so, the generic has passed its
bioequivalence test with respect to AUC values.
• However, the procedure must be repeated for maximum
plasma concentration (lnCpmax) data and, for some drugs, for
peak time data (tmax or lntmax) also, if the generic clears all
these hurdles, it is declared bioequivalent to the standard.
 ✌Thanks ✌

By : Hamid Hussein Hamid

NRU-Batch13
December 2017
✿✿✿