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Bioavailability and Bioequivalence
General concepts and overview
WHAT IS IT???
WHY IS IT???
HOW IS IT???
REGULATION VERSUS PHARMACEUTICAL COMP.
Generic Drug product: Definition
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Same active ingredient (s)
Same strength
Same dosage form
Same route of administration
Same indications
NDA vs. ANDA Review Process
Original Drug
NDA Requirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Animal Studies
7. Clinical Studies
(Bioavailability)
Generic Drug
ANDA Requirements
1. Chemistry
2. Manufacturing
3. Controls
4. Labeling
5. Testing
6. Bioequivalence Study (In Vivo, In
vitro)
Note: Generic drug applications are termed "abbreviated" because they are generally
not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness.
Instead, generic applicants must scientifically demonstrate that their product is bioequivalent
(i.e., performs in the same manner as the origina; drug).
FDA Definitions Used in Bioequivalence
Determinations
FDA Determinations of Bioequivalence
Main Terms
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Pharmaceutical equivalents
Pharmaceutical alternatives
Therapeutic equivalents
Bioavailability
Bioequivalence
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at:
http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September
Pharmaceutical Equivalents
• Drug products are considered pharmaceutical
equivalents if they contain the same active
ingredient(s), have the same dosage form and route of
administration, and are identical in strength or
concentration
• Equivalent products contain the same amount of
ingredient in the same dosage form but may differ in
characteristics, such as shape, release mechanisms,
and packaging
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site.
Available at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm. Accessed September 29, 2003.
Pharmaceutical Alternatives
• Drug products are considered pharmaceutical alternatives if
they contain the same therapeutic moiety, are different
salts, esters, or complexes of the same moiety, are different
dosage forms, or are different strengths
• Other pharmaceutical alternatives
– Different dosage forms and strengths within a single product line by a
single manufacturer
– Extended-release formulations when compared with immediate- or
standard-release formulations
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at:
http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September
29, 2003.
Therapeutic Equivalents
• Drug products are considered therapeutic equivalents if they
are all of the following
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Pharmaceutical equivalents
Bioequivalent
Approved as safe and effective
Adequately labeled
Manufactured in compliance with current Good Manufacturing Practice
regulations
• Therapeutic equivalents are expected to have the same
clinical effect and safety profile
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at:
http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September
29, 2003.
Bioavailability
(quantifies ABSORPTION = ?, Reasons for poor F)
• The extent and rate at which its active moiety is
delivered from pharmaceutical form and becomes
available in the systemic circulation
Pharmacokinetics
Conc.(mg/L)
conc. vs time
0.0
0
Time (h)
25
Why do we care about BIOAVAILABILITY?
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
Rate versus Extent of Absorption
Extent of absorption is reflected by AUC
Rate of absorption, ka, is reflected by Tmax
Both Rate and Extent of absorption affect Cmax
Leads to 4 possible relative scenarios:
􀂄 (R) Rapid, (E) Complete Absorption•
yields a short Tmax, high Cmax, high AUC
􀂄 (R) Rapid, (E) incomplete absorption•
yields a short Tmax, low Cmax, low AUC
􀂄 (R) Slow, (E) complete absorption•
yields a long Tmax, high Cmax, high AUC
􀂄 (R) Slow, (E) incomplete absorption•
yields a long Tmax, low Cmax, low AUC
FACTORS INFLUENCING BIOAVAILABILITY:
Three distinct factors are involved to influencing bioavailability. These are:
1.Pharmaceutical factors:
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physicochemical properties of the drug.
1. Particle size
2. Crystalline structure
3. Salt form
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Formulation and manufacturing variables.
1.Disintegration and dissolution time
2.Pharmaceutical ingredients
3.Special coatings
4.Nature and type of dosage form
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2. Patient related factors:
Physiologic factors.
1.Variations in pH of GI fluids
2.Gastric emptying rate
3. Intestinal motility
4. Presystemic and first-pass metabolism
5. Age, sex
6. Disease states
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Interactions with other substances.
1. Food
2. Fluid volume
3. Other drugs
3. Route of administration:
1.Parentral administration
2.Oral administration
3.Rectal administration
4.Topical administration
Bioequivalence
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A comparison of the bioavailability of two or more
drug products.
Two products or formulations containing the same
active ingredient are bioequivalent if their rates
and extents of absorption are the same
Bioequivalence may be demonstrated through in vivo or
in vitro test methods, comparative clinical trials, or
pharmacodynamic studies
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available
at: http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed
September 29, 2003.
Bioequivalence
Concentration (ng/mL)
90
80
70
60
T e s t / G e n e r ic
50
R e fe r e n c e / B r a n d
40
30
20
10
0
0
5
10
15
Time (hours)
20
25
30
Regulatory Bioequivalence: An Overview
Solutions
Suspensions
Chewable, etc.
Conventional
Tablets
Capsules
MR Products
“Self-evident” - Biowaivers granted
Condition- excipients do not alter absorption
(historical data)
Pre-1962 DESI Drugs: In Vivo
evaluation for “bio-problem”
drugs (TI, PK, P-Chem)
Post-1962 Drugs: Generally
In Vivo - some exceptions
(IVIVC..)
In VIVO
SUPAC-IR (1995)
Dissolution-IR
BCS
(pre-/post approval)
SUPAC-MR
IVIVC
Bioequivalence: IR Products
Pharmaceutical Equivalent
Products
Reference
Possible Differences
Test
Drug particle size, ..
Excipients
Manufacturing process
Equipment
Site of manufacture
Batch size ….
Documented Bioequivalence
= Therapeutic Equivalence
Hussain,
FDA spec.)
(Note: Generally, Ajaz
same
dissolution
Normal healthy subjects
Crossover design
Overnight fast
Glass of water
90% CI within 80-125%
of Ref. (Cmax & AUC)
FDA Methods to Determine
Bioequivalence
• Generic drug manufacturers must demonstrate
that a drug is bioequivalent to a reference drug
product
• In order of FDA preference, methods used to
define bioequivalence
– Pharmacokinetic studies
– Pharmacodynamic studies
– Comparative clinical trials
– In vitro studies
Food and Drug Administration. Code of Federal Regulations. Title 21, Part 320: Bioavailability and Bioequivalence
Requirements. Section 320.24. 2003. Available at: http://www.accessdata.fda.gov. Accessed September 29, 2003.
Pharmacokinetic Studies
Key Measurements
Concentration
Study Compound
Reference Compound
Cmax
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AUC
– Area under the concentration- time curve
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Cmax
– Maximum concentration
– A difference of greater than 20% in Cmax or
the AUC represents a significant difference
between the study and reference
compounds
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Tmax
– Time to maximum concentration
AUC
Tmax
Time
Approved Drug Products With Therapeutic Equivalence Evaluations. 23rd ed. 2003. FDA/CDER Web site. Available at:
http://www.fda.gov/cder/ob/docs/preface/ecpreface.htm#Therapeutic Equivalence-Related Terms. Accessed September 29, 2003.
Comparative Pharmacodynamic Studies
• Not recommended when:
– active ingredient is absorbed into the systemic
circulation
– pharmacokinetic study can be conducted
• Local action / no systemic absorption
• eg. : Topical Corticosteroid
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Hanoi, 2006-19-01
Comparative Clinical Studies
• Pharmacokinetic profile not possible
• Lack of suitable pharmacodynamic endpoint
• eg . : (Nasal suspensions)
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Hanoi, 2006-19-01
Study Designs
-Single-dose, two-way crossover design
- Single-dose, parallel design
-Multiple-dose studies( in case of :
-Drugs too potent/toxic
Extended/modified release products
Crossover vs. Parallel Designs
• Crossover design preferred
– Intra-subject comparison
– Lower variability
– Generally fewer subjects required
• Parallel design may be useful
– Drug with very long half-life
– Crossover design not practical
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Hanoi, 2006-19-01
Disadv. of cross over design
• The main problem with the cross over design is :
The carry over effect………!?
Fasted vs. Fed Designs
• Fasted study design preferred
– Minimize variability not attributable to formulation
– Better able to detect formulation differences
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Hanoi, 2006-19-01
Fed Study Designs may be employed when:
• Significant gastrointestinal (GI) disturbance caused
by fasted administration
• Product labeling restricts administration to fed state
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When equivalence studies are NOT
necessary (Biowaivers)
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• Aqueous parenteral solutions
• Solutions for oral use ( syrups, elixirs, tinctures & other
soluble forms but not suspensions)
• Pdrs for reconstitution as a solution
• Otic or ophthalmic aqueous solutions
• Topical aqueous solutions
• Aqueous nebulizing inhalations or nasal sprays
• B. For some products bioequivalence may be
demonstrated by evidence obtained in vitro instead
of in vivo data:
– The drug product is in the same dosage form, but in a
different strength, and is proportionally similar in its
active and inactive ingredients to another product by
the same manufacturer that was found to be
bioequivalent.
• For high potency drug substances, the same
inactive ingredients are used for all strengths, and
the change in any strength is obtained by altering
the amount of the active ingredients and one or
more of the inactive ingerdients are within the
limits defined by the SUPAC guidances (up to level
II).
Waiver of Bioavailability and
Bioequivalence Studies for ImmediateRelease Solid Oral Dosage Forms Based on
a Biopharmaceutics Classification System
(B.C.S)
BCS Classifications
According to the BCS, drug substances
are classified as follows:
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Class I - High Permeability, High Solubility
Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility
Solubility
• A drug substance is considered highly soluble when
the highest dose strength is soluble in 250 ml or
less of aqueous media over the pH range of 1 - 7.5
(WHO , pH: 1.2 – 6.8)
Permeability
• A drug substance is considered to be highly
permeable when the extent of absorption in
humans is determined to be 90% or more of an
administered dose ( WHO, 85% ).
Conditions for BCS Bio-waivers
Firms can request waivers of in vivo testing for Class
1 drug substances
Drug products must meet these criteria:
 Immediate-release solid oral dosage forms
 Highly soluble, highly permeable drug
substance
 Rapid in vitro dissolution
Note: Waivers not applicable for narrow therapeutic range therapeutic
range (Digoxin, Lithium, phenytoin, warfarin) drugs
A drug product is considered to be
RAPIDLY DISSOLVING when > 85% of
the labeled amount of drug substance
dissolves within 30 minutes using USP
apparatus I or II in a volume of < 900 ml
buffer solutions.
BCS Class I: Dissolution
 USP Apparatus I (100 rpm) or II (50 rpm)
 Three media
0.1 N HCl or SGF USP without enzymes 0.1 N
HCl or SGF USP without enzymes
pH 4.5 buffer pH 4.5 buffer
pH 6.8 buffer or SIF USP without enzymes
 NLT 85% dissolves within 30 minutes
 Similarity factor (f2) for test (T) v. reference
(R) profile comparisons should > 50