Download Week 6- Bioavailability and Bioequivalence

Week 6- Bioavailability and
Bioequivalence
Pn. Khadijah Hanim Abdul Rahman
School of Bioprocess Engineering
Universiti Malaysia Perlis
Bioavailability and Bioequivalance
• Bioavailability.
Bioavailability- 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.
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.
• Bioequivalence requirement.
A requirement imposed by the FDA for in-vitro
and/or in-vivo testing of specified drug
products, which must be satisfied as a
condition for marketing.
• Bioequivalent drug products.
describes pharmaceutical equivalent or
pharmaceutical alternative products that
display comparable bioavailability when
studied under similar experimental conditions.
• For systemically absorbed drugs, test drugs and
reference listed drug- considered bioequivalence
if:
1. the rate and extent of absorption of the test
drug do not show a significant difference from
the rate and extent of absorption of the
reference drug when administered at the same
molar dose of the therapeutic ingredient under
similar experimental conditions in either a single
dose or multiple doses
2. the extent of absorption of the test drug does not
show a significant difference from the extent of
absorption of the reference drug when administered
at the same molar dose of the therapeutic ingredient
under similar experimental conditions in either a
single dose or multiple doses.
- and the difference from the reference drug in the
rate of absorption of the drug is intentional, is
reflected in its proposed labeling, is not essential in
obtaining the effective body drug concentrations on
chronic use, and is considered medically insignificant
for the drug.
• PURPOSE OF BIOAVAILABILITY STUDIES
– Bioavailability studies are performed for both
approved active drug ingredients and therapeutic
moieties not yet approved for marketing by the
FDA.
– New formulations of active drug ingredients must
be approved by the FDA before marketing. In
approving a drug product for marketing, the FDA
ensures that the drug product is safe and effective
for its labeled indications for use.
– The drug product must meet all applicable
standards of identity, strength, quality, and purity.
• Bioavailability- considered as an aspect of drug product
quality
Links to in-vivo performance of drug product used in
clinical trials- evidence of safety and efficacy
• pharmacokinetics parameters: rate and extent of
systemic absorption, elimination half-life and rates of
excretion and metabolism- established after single and
multiple dose
• Data from in-vivo bioavailability- important to
established recommended dosage regimens and drug
labeling.
• Summary:
• Bioavailability- to define the effect of changes in
physicochemical properties of drug substance
and effect of dosage form on pharmacokinetics of
the drug.
• Bioequivalence- to compare the bioavailability of
the same drug from various drug products.
• Bioavailability and bioequivalence- performance
measures of drug product in-vivo.
Relative and absolute availability
• AUC (area under the drug
concentration) time curve is
used as a measure of the total
amount of unaltered/active
drug that reaches the
systemic circulation.
• The AUC is dependent on the
total quantity of available
drug, FDO, divided by the
elimination rate constant, k,
and the apparent volume of
distribution, VD.
• After IV, F=unity.
• After oral administration- F
vary from 1 to 0.
FD0
AUC 
kVD
 Concentrat ion X time
Relative availability
Relative (apparent) availability- availability of
the drug from a drug product as compared to
a recognized standard.
• For oral absorption drug- difficult to
determine the availability- availability of drug
in formulation is compared to availability of
drug in a standard dosage formulation.
Relative Availability
• The relative availability of two drug products given at
the same dosage level and by the same route of
administration can be obtained using the following
equation:
• B- product B- the recognized reference standard
Relative Availability
• When different doses are administered, a correcting
the dose size
• The percent relative availability using urinary
excretion data
• [Du]∞ - total amount of drug excreted in urine
Absolute Availability
• The absolute availability- drug is the systemic
availability of a drug after extravascular
administration (e.g., oral, rectal, transdermal,
subcutaneous) compared to IV dosing.
• The absolute availability of a drug - generally
measured by comparing the respective AUCs after
extravascular and IV administration.
• This measurement may be performed as long as VD
and k are independent of the route of
administration.
Absolute Availability
• Absolute availability after oral drug administration
using plasma data can be determined as follows:
• Absolute availability using urinary drug excretion
data can be determined by the following:
• Example:
• The bioavailability of a new investigational drug was
studied in 12 volunteers. Each volunteer received
either a single oral tablet containing 200 mg of the
drug, 5 mL of a pure aqueous solution containing 200
mg of the drug, or a single IV bolus injection containing
50 mg of the drug. Plasma samples were obtained
periodically up to 48 hours after the dose and assayed
for drug concentration. The average AUC values (0-48
hours) are given in the table below. From these data,
calculate (a) the relative bioavailability of the drug
from the tablet compared to the oral solution and (b)
the absolute bioavailability of the drug from the tablet.
Drug Product
Oral tablet
Oral solution
IV bolus injection
Dose (mg)
200
200
50
AUC (mg hr/mL)
89.5
86.1
37.8
Standard Deviation
19.7
18.1
5.7
• The relative bioavailability of the drug from the
tablet is
• The absolute drug bioavailability from the tablet is
Methods for assessing bioavailability
• Direct and indirect methods
• In-vivo bioavailability- demonstrated by rate
and extent of drug absorption- determined by
comparison of measured
• Pharmacokinetics/ pharmacodynamic
parameters, clinical observations, in-vitro
studies- used to determine drug bioavailability
from a drug product.
METHODS FOR ASSESSING BIOAVAILABILITY
Plasma drug concentration
• Systemic drug bioavailability- measurement of drug
conc in blood, plasma or serum after drug
administration
• tmax- time of peak plasma conc- time required to reach
max drug conc after drug administration
• At tmax- peak drug absorption occurs: rate of drug
absorption=rate of drug elimination
• Drug absorption still continues after tmax- slower rate
• Comparing drugs- tmax can be used as indicator of drug
absorption rate
• tmax become smaller- absorption rate becomes more
rapid.
Plasma Drug Concentration-time curve
Cmax- peak plasma drug concentration
• Cmax- indicates the drug is sufficiently
systemically absorbed to provide therapeutics
response.
• Cmax- provides warning of possibly toxic levels
of drug
AUC- area under the curve
• AUC- measurement of extent of drug
bioavailability
• AUC- total amount of active drug that reaches
systemic circulation
• AUC- AUC from t=0 to t=∞, equal to amount
of unchanged/active drug reaching general
circulation divided by clearance.
• AUC proportional to dose.
• E.g. single dose of drug is increased from 2501000 mg, the AUC also- 4 fold increase.
Urinary Drug Excretion Data
• Indirect method for estimating bioavailability
• Drug excreted in significant quantities as
unchanged drug in urine.
• Du∞- cumulative amount of drug excreted in
the urine- related directly to the total amount
of drug absorbed
• Relationship between cumulative amount of
drug excreted in urine and plasma level-time
curve:
When drug is almost completely
eliminated (point C), plasma
conc approaches 0- Du∞ is
obtained.
• dDu/dt- rate of drug excretion.
• Most drugs- eliminated by 1st order process.
• Rate of drug excretion- dependant on 1st order
elimination rate constant, k and plasma conc,
Cp.
•(dDu/dt)max- at point B,
•(dDu/dt)min- at point A and C
•Thus, a graph comparing rate of drug
excretion with respect to time should
de similar shape as plasma level-time
curve.
• t∞- total time for the drug to be excreted.
• The slope of the curve segment A-B (from the
graphs)- related to rate of drug absorption
• Point C- total time required after drug
administration for the drug to be absorbed
and completely excreted t=∞.
Bioequivalence studies
• Bioequivalent drug products- same systemic
drug bioavailability- same predictable drug
response
• Variable clinical responses among individualsunrelated to bioavailability- due to differences
in pharmacodynamicsof drug
• Difference in pharmacodynamics- differences
in receptor sensitivity to the drug.
Bases for determining bioequivalence
• Bioequivalence- established if, in-vivo
bioavailability of test drug product- does not
differ significantly in rate and extent of
absorption when administered at the same
molar dose under similar experimental
condition, either single dose or multiple dose.
DESIGN AND EVALUATION
OF BIOEQUIVALENCE STUDIES
• Bioequivalence studies- to compare the bioavailability of
generic drug product to brand-name product.
• Once bioequivalence established- likely both generic and
brand-name dosage forms, produce the same therapeutic
effect.
• The basic design for a bioequivalence study is determined
by
1.
2.
3.
4.
The scientific questions to be answered,
The nature of the reference material and the dosage form to
be tested,
The availability of analytical methods, and
Benefit–risk and ethical considerations with regard to testing
in humans. For some generic drugs, the FDA offers general
guidelines for conducting these studies
• For bioequivalence studies- test and reference
drug formulations must contain:
- Pharmaceutical equivalent drug
- In the same dose strength
- In similar dosage forms (e.g:
Immediate/controlled release)
- The same route of administration
Analytical Methods
• Analytical method used in an in-vivo
bioavailability or bioequivalence study- must be
demonstrated to be:
- accurate
- sufficient sensitivity
- with appropriate precision
• For bioavailability studies- both parent drugs and
major active metabolites are studied
• For bioequivalence studies- parent drug is
measured.
Reference Standard
• For bioequivalence studies:
- One formulation of drug is chosen as
reference standard
- Reference drug product- should be
administered by the same route unless an
alternative route is needed.
Study Design
• Three different studies may be required for
solid oral dosage forms,
(1) a fasting study,
(2) a food intervention study, and/or
(3) a multiple-dose (steady-state) study.
Crossover Designs
• Subjects are selected at random
• Complete crossover design is usually
employed- each subject receives the test drug
product and reference product.
• E.g. Latin-square crossover designscomparing 3 different drug formulations (A, B,
C)
• Plans the clinical trial- each subject receives
each drug product only once
• All patients do not receive the same drug
product on the same day and in the same
order
• After each subject receives a drug productblood samples are collected at appropriate
time intervals
• Time intervals should be spaced- peak blood
conc, total AUC and absorption/elimination
phases may be well described.
Evaluation of the data
• Analytical Method
- Must be accurate, precision, sensitive and
specific
- Only one method is implemented during
bioequivalence study
- Data- in tabulated and graphic form
Statistical Evaluation of the data
• Bioequivalence- determined using a
comparison of population averages of
bioequivalence metric, such as AUC and Cmax
• To established bioequivalence- calculated
confidence interval should be between 80125% (for ratio of the product averages).
• There must be no statistical difference
between bioavailability of test product and
reference product
• Pharmacokinetic Evaluation of the data
- For single-dose studies (including fasting
study/ food intervention study)pharmacokinetic analyses include calculation
for each subject:
-AUC (AUC0-t), (AUC0-∞)
-tmax and Cmax
-k, t1/2 and other parameters may be estimated
Bioequivalence example
• No statistical differences for pharmacokinetics parameters.
• 90% confidence limit-within 80-125% of reference products
• The power test for AUC were above 99%- good precision of data
• The power test for Cmax was 87.9%- this parameter was more variable.
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