BIOAVAILABILITY AND

BIOEQUIVALENCE
BY; Amanuel W
Email:[email protected]

01/21/25 1
 BIOAVAILABILITY AND
BIOEQUIVALENCE

Introduction and terminologies

 Types of bioavailability (absolute, relative)
Methods of Assessing Bioavailability
 Bioequivalence studies

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 Introduction and terminologies
 Pharmaceutical equivalents
• Contain same amount of active substance(s), i.e., same salt or
ester form, in same DF that meet same or comparable
standards (i.e., strength, quality, purity, and identity)
• May differ in excipients (including colors, flavors,
preservatives), characteristics such as shape, scoring
configuration, release mechanisms, packaging, expiration
time, and, within certain limits, labelling

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 Cont…
Pharmaceutical alternatives
 Contain same therapeutic moiety but as different salts, esters, or
complexes

e.g., TTC PO4 and TTC HCl equivalent to 250 mg base

 Different DFs and strengths within product line by single
manufacturer are pharmaceutical alternatives

e.g., Extended-release DF and Standard Immediate-release DF

of same active ingredient
Tablet and Capsule DFs containing same active ingredient
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 Cont…
Bioequivalents
 Describes pharmaceutical equivalent or
pharmaceutical alternative
Products that display comparable bioavailability
when administered in same molar dose to such degree
that their effects with respect to both efficacy and
safety is essentially same

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 Cont…

Reference listed drug

 Approved drug product to which new generic
versions are compared to show that they are
bioequivalent.

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 Con…
Therapeutic equivalents
 Contain same therapeutically active drug that should give same
therapeutic effect and have equal potential for adverse effects under
conditions set forth in the labels of these products
 Therapeutic equivalent drug products must be (FDA)
(1) Approved as safe and effective
(2) Pharmaceutical equivalents
(3) Bioequivalent
(4) Adequately labelled; and
(5) Manufactured in compliance with CGMP regulations

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 Con…
Therapeutic alternatives
 Contain different active ingredients that are
indicated for same therapeutic or clinical objectives
– Active ingredients are from same pharmacologic
class and are expected to have same therapeutic effect
when administered to patients
Ibuprofen is given instead of Aspirin
Cimetidine may be given instead of Ranitidine

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 Con…
• Brand-name drug
 Drug that has trade name and is protected by patent
(exclusive right), that can be produced and sold only by
innovator company holding patent (10-15 yrs).
• Generic drug
 Pharmaceutical product, usually intended to be interchangeable
with innovator product, that is manufactured without license
from innovator company and marketed after expiry date of
patent.
 marketed under non-proprietary (INN) or approved name rather
than proprietary or brand name

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 Con…
• Test products
 May be new drug formulation or new DF of existing drug
 Produced with CGMP compliance
• Reference standard
 FDA/EMA/WHO accept innovator drug product as reference
standard
 Product which originally received approval for marketing
 Used in clinical efficacy and safety studies

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• DRUG PRODUCT DEVELOPMENT AND APPROVAL PROCESS

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 RELATIVE AND ABSOLUTE BIOAVAILABILITIES
• Bioavailability of drug from DF is critical element of drug
product's clinical efficacy.
- Pharmacologic response is generally related to conc. of drug at
receptor site.
• Drug conc usually cannot be readily measured at site of action.
• Most bioavailability studies involve determination of drug conc. in
blood or urine
Drug at site of action is in equilibrium with drug in blood
Indirect measures of drug response
•36

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 RELATIVE AND ABSOLUTE
BIOAVAILABILITIES

 Bioavailability is concerned with how quickly and how much of

drug appears in blood after specific dose is administered.
 In most cases, it concerns with fraction of dose that actually
reaches bloodstream represents ‘effective dose’ of drug.
 ‘Absolute bioavailability’ F, is fraction of administered dose
which actually reaches systemic circulation

 Generally, less than amount of drug actually administered

 F = 0 (no drug absorption) to F = 1 (complete absorption)

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 RELATIVE AND ABSOLUTE BIOAVAILABILITIES

 Absolute bioavailability of drug is systemic availability of drug after

extravascular administration (e.g., oral, rectal, transdermal, subcutaneous)

compared to IV route.
 IV is reference standard as dose is completely available.

 Absolute bioavailability after oral drug administration using plasma data

can be determined as follows:

Absolute Bioavailability

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 RELATIVE AND ABSOLUTE BIOAVAILABILITIES

• Considering possibility of different doses:

• Absolute Bioavailability

=(Constant clearance - Vd and k are independent

of route of administration)

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 RELATIVE AND ABSOLUTE BIOAVAILABILITIES
 Urinary drug excretion data may also be used to measure
bioavailability
 total amount of intact drug excreted in urine is collected
• Absolute Bioavailability

where
• [Du]∞ is total amount of drug excreted in urine
• PO is oral or any other extravascular route
N.B. Knowledge of F is needed to determine appropriate
extravascular/ oral dose of drug relative to IV dose

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 RELATIVE AND ABSOLUTE BIOAVAILABILITIES

• Relative’ or ‘Comparative’ or ‘Apparent’

bioavailability (Frel) refers to availability of drug
product as compared to recognized standard.
• Relative bioavailability of product A compared
to product B, is given by
• Relative Bioavailability

where drug product B is reference/recognized

standard
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 RELATIVE AND ABSOLUTE BIOAVAILABILITIES
 The percent relative bioavailability using
urinary excretion data can be determined as
follows:
• Percent Relative Bioavailability
• where [Du]∞ is total amount of drug
excreted in urine
 Frel = 0 (no absorption) to Frel = 1 (equal
absorption) to Frel > 1 (more drug absorption)

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 PURPOSES OF BIOAVAILABILITY STUDIES

 For both approved active drugs and therapeutic moieties not yet
approved for marketing by regulatory authorities.
 BA/BE studies are of particular interest to both innovator and
generic drug companies in following ways:
•For new drugs To establish essential PK parameters including

– rate and extent of systemic absorption

– rates of excretion and metabolism

– elimination half-life

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 cont…
 To establish dosage regimens
– Dose, Frequency of administration
– Treatment duration
 To determine influence of
 manufacturing procedures
 excipients
 patient-related factors on biological performance of new drug
formulation
 To establish drug product safety and efficacy
 Drug product must meet all applicable standards of identity, strength,
quality, and purity
 Subject to all applicable official laboratory tests
 Bioavailability/PhK studies to ensure safety and efficacy

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 Methods of Assessing Bioavailability
Parameters
Pharmacokinetic endpoint
 Plasma drug concentration data
– Peak plasma drug concentration (Cmax)
– Time for peak plasma (blood) concentration (tmax)
– Area under plasma drug concentration–time curve (AUC)
 Urinary drug excretion data
– Cumulative amount of drug excreted in urine
– Rate of drug excretion in urine
– Time for maximum urinary excretion

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 Methods of Assessing Bioavailability
 Acute pharmacodynamic effect
– Maximum pharmacodynamic effect
– Time for maximum pharmacodynamic effect
– Area under pharmacodynamic effect-time curve
– Onset time for pharmacodynamic effect
 Clinical observations
– Well-controlled clinical trials
 In vitro studies

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 A. Plasma drug concentration data
 Most widely used and accepted method for assessing
bioavailability
Cmax and tmax are measures of rate of absorption
AUC is measure of extent of absorption

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 Methods of Assessing Bioavailability …
 Cmax - maximum plasma drug conc.

 For many drugs, relationship is found between plasma drug

conc. and pharmacodynamic effect
• Cmax provides indications that drug is sufficiently
systemically absorbed to provide therapeutic response
• Cmax provides warning of possibly toxic levels of drug
• Cmax is often used in bioequivalence studies as surrogate
measure for rate of drug bioavailability.

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 cont…
 tmax - time required to reach maximum drug conc.

 At tmax,

– Peak drug absorption occurs

– Rate of absorption exactly equals rate of drug elimination

– Drug absorption still continues after tmax is reached, but at slower

rate tmax can be used as approximate indication of absorption rate
  tmax become smaller as absorption rate becomes more rapid

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 Cont…
• AUC - measurement of extent of drug
bioavailability
• Reflects total amount of active drug that
reaches systemic circulation
• AUC is area under plasma level-time curve
from t = 0 to t = ∞,

• where t is the last time point of blood sample

collection
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• [AUC]0 t is calculated by trapezoidal rule;
[AUC]0t = (1/2) (C0+C1) (t1-t0) + (1/2) (C1+C2) (t2-t1) + …
+ (1/2) (Cn-1+Cn) (tn-tn-1)

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 Cont…
• Urinary Drug Excretion Data
• Based on general observation that rate of
urinary excretion of drug is directly
proportional to conc. of drug in blood
• Drug must be excreted in significant quantities
as unchanged drug in urine

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 METHODS OF ASSESSING BA/BE
Different methods are used to assess drug bioavailability:
I. Pharmacokinetic endpoint
 Plasma drug concentration data
 Urinary drug excretion data
II. Pharmacodynamic endpoint
 Acute pharmacodynamic effect
III. Clinical endpoint
 Clinical observations
IV. In vitro endpoint
 In vitro studies

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 Bioequivalence studies
WORKFLOW OF BA/BE STUDIES

•Before clinical trial is conducted, a protocol that details

conduct of the trial is usually developed.
•The protocol usually also gives background and rationale
for study.
•A thoughtful and well-organized protocol includes study
objective(s), design, subject selection criteria, dosing
schedules, and statistical methods.
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 ELEMENTS OF BA/BE STUDY PROTOCOL
I. Title
A. Principal investigator and Co-investigators
B. Project/protocol number and date
II. Study objective – what?
III. Study design – how?
A. Design
B. Investigational products
1. Test product(s)
2. Reference product
C. Housing/confinement
D. Fasting/meals schedule 7
E. Analytical methods
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 ELEMENTS OF BA/BE STUDY PROTOCOL…
IV. Study population
A. Subjects
B. Subject selection
1. Medical history
2. Physical examination (height, weight, 12-lead ECG)
3. Vital signs (blood pressure, heart rate, temperature)
4. Laboratory tests (hematology, urinalysis, pregnancy, serology)
C. Inclusion/exclusion criteria
1. Inclusion criteria
2. Exclusion criteria
D. Restrictions/prohibitions
V. Clinical procedures
A. Dosage and drug administration
B. Biological sampling schedule and handling procedures
C. Activity of subjects
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 ELEMENTS OF BA/BE STUDY PROTOCOL…
VI. Ethical considerations
A. Basic principles: “Declaration of Helsinki”
B. Institutional review board
C. Informed consent
D. Indications for subject withdrawal
E. Adverse reactions and emergency procedures
VII. Facilities
VIII. Data analysis
A. PK data analysis
B. Statistical treatment of data
IX. Drug accountability
X. Appendix
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Cross-over vs parallel design

• Parallel study design

• Each subject is administered only one treatment, resulting in a product
BE assessment based upon a between-individual comparison.
• Intersubject variability + intrasubject variability + random error
contribute to the uncertainty associated with the (population) prediction
of mean test/reference ratios
Test period
Group 1 Test
Group 2 Reference
• Cross-over study design
• Each subject is administered both the test and reference formulations,
resulting in a product BE assessment based upon a within-individual
comparison.
• Intersubject variability does not contribute to the uncertainty
associated with the (population) predictions of mean test/reference
ratios
Sequence A Sequence B

Period 1 Test Reference

Period 2 Reference Test
Washout period
• Time interval between treatments is called ‘washout period’
Washout period is required for elimination of administered drug
so as to avoid carryover (residual) effect
• Washout period is function of half-life
• For most drugs, period of at least 10 half lives should be allowed
 Elimination of 99.9% of administered dose
 Max. carryover of less than 0.1% from first treatment
Carry-over effects
 The potential for carry-over can be directly addressed by
examination of pre-treatment plasma concentrations in period 2
(and beyond, if applicable).
 If there are any subjects for whom pre-dose concentration is
greater than 5% of Cmax value for subject in that period, data
from that subject for that period should be excluded from
statistical analysis.
 In 2-period trial, this will result in subject being removed from
analysis
Selection of subjects
Thank you!