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Bioavailability & Bioequivalence

Bioavailability & Bioequivalence:


Pharmacokinetic Principles

Sandip K. Roy, Ph.D.


Exploratory Clinical Development – PK
Novartis Pharmaceutical Corporation

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

 Pharmacokinetics  Pharmacodynamics
 “what the body does to the drug”  “what the drug does to the body”
 Absorption  wanted effects - efficacy
 Distribution  unwanted effects - toxicity
 Metabolism
 Elimination

disposition

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Pharmacokinetics Pharmacodynamics

Dose regimen Exposure Response


Site of action

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Bioavailability & Bioequivalence

Pharmacokinetics is either directly or


indirectly associated with just about
every part of pharmaceutical business:

 Research and the selection of a promising molecule


 Dosage formulation development
 Dose regimen
 Toxicology and safety assessment
 Dosing recommendations for age groups & sub-populations
(renal/hepatic/race/DDI)
 Effect of meals and dosing
 Marketing claims and promotion
 Generic substitution
 Manufacturing changes

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Bioavailability & Bioequivalence

General Outline
 Basic Pharmacokinetic Concepts

 Bioavailability
Definition
How absorption affects bioavailability?
Food Effect
How drug metabolism affects bioavailability?
How transporters affect bioavailability?

 Bioequivalence
Definition
Bio-IND
Waivers of In Vivo Study Requirements
Biopharmaceutics Classification System (BCS)

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Bioavailability & Bioequivalence

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Basic Concepts
 Easy to understand using intravenous route
Drug Product
 No absorption phase
 Simple to follow
 Concepts clear with less assumptions

Drug in Distribution to
Blood Tissue and Receptor sites

 Need some math background


Excretion Metabolism
 algebra, log scale, Simple linear Equations etc
 complex math (differential equations, statistical
concepts etc) for Modeling, Population PK,
PK-PD etc.

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Bioavailability & Bioequivalence

IV administration, contd.,

 Following dose administration, we need to


follow its drug’s disposition to understand Blood withdrawal

its PK characteristics.
 This is achieved by analyzing the changes
of the drug and/or its metabolite(s) in
blood, plasma, urine etc.
 A simple approach is to generate Drug
Concentration-Time profile

Sampling at
Dosing Bio-analytics Conc. vs time
Pre-determined
profiles
Time intervals

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Bioavailability & Bioequivalence

Concentration versus Time Profiles


Broadly the concentration – time profiles can be viewed as two different ways

One-Compartment Model Dose


1
Assumes body as one compartment

Two-Compartment Model
Dose
Central compartment (drug entry and elimination) 1 2
Tissue compartment (drug distributes)

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Bioavailability & Bioequivalence

 The one compartment model linear


assumes that the drug in question is
evenly distributed throughout the body
into a single compartment.

 This model is only appropriate for drugs


which rapidly and readily distribute
between the plasma and other body
tissues.

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Bioavailability & Bioequivalence

The distribution phase for aminoglycosides is only 15-30


minutes, therefore, we can use a one-compartment model with a
high degree of accuracy

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Bioavailability & Bioequivalence

 Drugs which exhibit a slow


equilibration with peripheral
tissues, are best described with a
two compartment model

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Bioavailability & Bioequivalence

Vancomycin is the classic example, it's distribution phase is 1 to 2 hours.


Therefore, the serum level time curve of vancomycin may be more accurately
represented by a 2-compartment model.

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Bioavailability & Bioequivalence

Volume of Distribution
 The concentration in plasma is achieved after distribution is complete is a function of dose
and extent of distribution of drug into tissues

 This extent of distribution can be determined by relating the concentration obtained with a
known amount of drug in the body

 Concentration is related to the amount by a constant, VOLUME (V)


Amount (mg) = C (mg/L) * V (L)
OR V = Amount / C
V is known as Apparent Volume of distribution.

Plasma volume ~ 3 L; Extracellular water ~16 L; Total body water ~ 42 L

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Bioavailability & Bioequivalence

Volume of Distribution
Case -1
 At Time zero, the drug amount in the body is the dose (500 mg)
 Calculated drug concentration at Time zero is 50 mg/L
 Then, the V = 10 L
Case -2
 Dose = 500 mg
 Calculated Concentration at time Zero is 5 mg/L
 Then, V = 100 L

Examples: Ibuprofen: V is 10 L; Diovan 17 L; Digoxin: ~500L;


Chloroquin: 15000 L

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Bioavailability & Bioequivalence

Area Under the Concentration – Time Curve (AUC)


 A quantitative measure for exposure from
Concentration (Units/ml)

dosing time to time ‘t’


10
 An important parameter in PK
1  AUC(t) and AUC(inf)
 Determined by trapezoidal method
0.1
 AUC(inf) = AUC(t) + Ct/k
0.01 Units: Conc*t (mg/L * h)
0 5 10 15 20
 Proportional to Dose (linear PK)
Time (hr)  Accuracy of the estimate depends on
frequency of sampling
Area Under the Curve (AUC)

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Bioavailability & Bioequivalence

How is drug excreted/eliminated?


 The Kidneys
This is the main excretory organ for drugs
The Nephron: Glomerulus, proximal tubule, loop of Henle, distal
tubule, and collecting tubule
 Drug enters the lumen of the nephron by filtration and secretion
 Filtration occurs in the glomerulus; secretion is primarily restricted
to the proximal tubules
 Reabsorption occurs all along the nephron; Active reabsorption
usually occurs in the proximal tubule
 Appearance of drug in the urine is the net result of filtration,
secretion, and reabsorption

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Bioavailability & Bioequivalence

Drug metabolism/biotransformation

 This mainly occurs in the liver, via liver enzymes.


 But it can also occur in the blood plasma or at various other
places (stomach, intestines, lungs, skin, or kidneys) directly
by various enzymes at those locations
 In any case, these metabolites are then excreted/eliminated
(more easily than would the parent molecule have been)
metabolites are often smaller in size, ionized
 Some drugs are excreted/eliminated in unmetabolized
form, as the original drug molecule (e.g. Lithium)

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Bioavailability & Bioequivalence

Other Routes of Excretion/Elimination

 In bile (which then empties into gut, excreted in


feces)
[can excrete from 5 to 95% of drug dose, esp. antibiotics]

 In sweat, saliva, tears, exhaled breath, milk, hair,


nails
[as heart rate increases --- pulmonary circulation --- which then
increases amounts of breath exhaled --- more drug eliminated]

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Bioavailability & Bioequivalence

Concept of “Half Life”

 ½ life = how much time it takes for blood levels of drug to decrease to half
of what it was at equilibrium
 There are really two kinds of ½ life…
“distribution” ½ life = when plasma levels fall to half what they were
at equilibrium due to distribution to/storage in body’s tissue reservoirs
“elimination” ½ life = when plasma levels fall to half what they were
at equilibrium due to drug being metabolized and eliminated
 It is usually the elimination ½ life that is used to determine dosing
schedules, to decide when it is safe to put patients on a new drug

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Bioavailability & Bioequivalence

Concept of “Half Life”

4
C o n c . [m g /L ]

0 4 8 12 16 20 24

Time [hours]

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

Elimination

ke 
lny  ln y
2
T1/2

lny  lny  ln2


ke 
T1/2

ln2
ke 
T1/2

0.693
ke 
T1/2

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Bioavailability & Bioequivalence

“Rule of Five”

5x the elimination ½ life = time at which the drug is


“completely” (97%) eliminated from the body
1x ½ life - 50% of the original drug removed
2x ½ life - 75%
3x ½ life - 87.5%
4x ½ life - 93.75%
5x ½ life - 96.875%

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Bioavailability & Bioequivalence

Clearance

“Of the concepts in pharmacokinetics, clearance has the greatest potential


for clinical applications.
It is also the most useful parameter for the evaluation of an elimination
mechanism.”

Rowland & Tozer

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Bioavailability & Bioequivalence

Clearance

 Quantifies Elimination

 Is the volume of body fluid cleared per time


unit (L/h, mL/min)

 Is Usually Constant

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Bioavailability & Bioequivalence

Clearance
Proportionality factor relating rate of drug elimination to plasma
drug concentration

Rate of eliminatio n  CL  C

Rate of eliminatio n
CL 
C
(dx/dt)
CL 
C
Integrate
DoseIV
CL 
AUC
Bioavailability & Bioequivalence, June 2, 2004
Bioavailability & Bioequivalence

Clearance
Rate of elimination is proportional to the amount (A) of drug present

Rate of eliminatio n  k * A

Rate of eliminatio n  k * V * C

Rate of eliminatio n
k*V
C
Clearance  k * V
0.693 * V
Clearance 
Half - life

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Bioavailability & Bioequivalence

Dependence of Half-life on
Clearance and Volume

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Bioavailability & Bioequivalence

Why is Clearance Important?

Clearance is the one parameter that determines the


maintenance dose rate required to achieve a desired
plasma conc.

Dosing rate = clearance X desired plasma conc.

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Bioavailability & Bioequivalence

For a given dose rate, the blood drug concentration is inversely


proportional to clearance

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Bioavailability & Bioequivalence

Multiple Dose Administration


Concentration

Time (hr)
 Minimum and maximum conc should be within therapeutic window – depends on dose,
frequency and t1/2
 Depending on dosing frequency and t 1/2, accumulation occurs
 Degree of accumulation is important for safety assessment purposes

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Bioavailability & Bioequivalence

Bioavailability and Its Assessment


Bioavailability: The rate and extent to which the parent
compound reaches the general circulation.

Absolute Bioavailability

 requires I.V. administration


 Ratio of the oral:intravenous AUC values normalized for dose
 Fabs= (AUC oral / AUC iv)*(Dose iv / Dose oral)

Relative Bioavailability

 no I.V. reference
 comparison AUC values (ratio) of different dosage forms / formulations
 Frel = (AUC a / AUC b) * (Dose b /Dose a)

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Bioavailability & Bioequivalence

5 5

4 4

Solution
Capsule

Conc. [mg/L]
Conc. [mg/L]

3 3

2 2

1
1

0
0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time [hours] Time [hours]

20 mg administered as an i.v. 80 mg given as a solution and a


bolus (Diovan) capsule (Diovan)

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Bioavailability & Bioequivalence

F=0.6

F=0.4*
16
14
F=0.2*
12
10

AUC
8
6

4
2
0
I.v. (20 mg) P.O. (80 mg) P.O. (80 mg)
Capsule Solution

*dose - adjusted

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Bioavailability & Bioequivalence

Anatomical Considerations
Gut Lumen

Portal Vein

Liver
Gut Wall
Systemic
Circulation
Metabolism Metabolism

Release + Dissolution

Permeation Elimination
Absorption
Bioavailability

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Bioavailability & Bioequivalence

How Absorption affects


Bioavailability?

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Bioavailability & Bioequivalence
Absorption
 Absorption is defined as the process by Absorption
which a drug proceeds from the site of
administration to the site of Drug Product
measurement.

 Drugs are frequently administered


extravascularly
Distribution to Tissue
 oral, sublingual Drug in
 intramuscular, and Receptor sites
Blood
 topical, patches, inhalation

 Absorption is a prerequisite for a drug


to exert it’s pharmacologic effect (other Metabolism
Excretion
than local effect)

 Several possible sites contribute to the


loss

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Bioavailability & Bioequivalence
Plasma Concentration-Time Profile for a Drug Following a
Single Oral Dose
Rate of drug accumulation at any
time:
dDBODY/dt= dDABS/dt - dDELIM/dt

Absorption Phase:
dDABS/dt > dDELIM/dt

At time of peak drug conc.:


dDABS/dt = dDELIM/dt

Post-absorption Phase:
dDABS/dt < dDELIM/dt
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Bioavailability & Bioequivalence

Physiological Considerations
 Surface area
 small intestine = 200 m2
 stomach = 1 m2
 Permeability
 intestinal membrane>stomach
 Blood flow (for perfusion rate-limited absorption)
 small intestine = 1000 mL/min through intestinal
capillaries
 stomach = 150 mL/min
 Gastric emptying and pH
 GI transit
 Rate of gastric emptying is a controlling step for
rapid absorption

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Bioavailability & Bioequivalence

Physico-Chemical Factors

 Partition Theory

 Ionization, pH-pKa Relationship

 Polymorphism

 Particle Size

 Complexation

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Bioavailability & Bioequivalence

Absorption Involves Movement Through Membranes


Efflux Influx

 Passive diffusion
 Active transport
 Rate of diffusion = P *(C1-C2)
where P is permeability coefficient
 Lipophilicity (partition between oil
and water)
 Hydrophilicity (paracellular
movement depends on size, shape
and charge)

Transcellular
Paracellular
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Bioavailability & Bioequivalence

Passive Diffusion of Molecules

Passive diffusion

1 2

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Bioavailability & Bioequivalence

Comparison of the Rates of Drug Absorption

A = Passive diffusion
B = Active transport/

carrier mediated
system

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Bioavailability & Bioequivalence

Percent Dose Absorbed vs. Human Permeability


Naproxen
Piroxicam
Propanolol Ketoprofen
L-leucine

Percent Absorbed (%)


 Very low concentration
 No saturation effects
Phenylalanine
 Already in solution Benserazide D-glucose
 No dissolution effects L-Dopa
Metoprolol Antipyrine

Terbutaline
Furosemide

Atenolol
Enalaprilate

Human Permeability (104, cm/sec)

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Bioavailability & Bioequivalence

Effect of Blood Flow on Absorption

blood blood

membrane

tissue tissue

 If the membrane offers no  High resistance to drug


resistance movement
 movement is dependent on  movement insensitive to
blood flow changes in perfusion

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Bioavailability & Bioequivalence

pH – pKa Ionization

Weak acid
pka - pH = log [(un-ionized)/(ionized)]

Weak base
pka - pH = log [(ionized)/(un-ionized)]

Examples:
Aspirin, pka : 3.5, at pH = 1, mostly unionized
Phenytoin, pka : 8.3, unionized in stomach
Diazepam, pka : 3.3, mostly ionized in stomach
Procainamide, pka : 9.5, mostly ionized in stomach

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Bioavailability & Bioequivalence

Gastrointestinal pH and Transit Time in the


Fasted State
Re g io n pH Re sid e nc e
tim e
Sto m a c h 1.5-2 0-3 h o u rs

Du o d e n u m 4.9-6.4 3-4 h o u rs

Je ju n u m 4.4-6.4 3-4 h o u rs

Ille u m 6.5-7.4 3-4 h o u rs

C o lo n 7.4 Up to 18 h o u rs

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Bioavailability & Bioequivalence
Assessment of Drug Absorption

 Absorption is measured as Rate of Absorption, ka. and Extent (AUC)


 For Rate - Need to fit the data and it is model dependent
 A surrogate is Cmax/AUC
 Example:
Lescol capsule (IR) : 0.37 hr-1
Lescol XL: 0.19 hr-1

 Usually (also) measured as Cmax and Tmax


Cmax Tmax
Lescol IR 438 0.5-1 h
Lescol XL 101 1.5-4 h

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Bioavailability & Bioequivalence

Effect of a Change in Absorption Rate Constant (Ka) on Plasma Drug


Concentration Versus Time Curve

0.5/hr

0.2/hr

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Bioavailability & Bioequivalence

Interactions in Oral Drug Absorption

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Bioavailability & Bioequivalence

Pharmacokinetic Assessment of Absorption


Interactions

Clinically significant interactions are typically


assessed in terms of:

Rate of Absorption:
 peak plasma drug concentrations (Cmax)
 time to Cmax (tmax)

Extent of Absorption:
 area under the concentration-time curve (AUC)

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Bioavailability & Bioequivalence
Effect of Absorption Interactions on Drug Plasma
Concentration Profiles

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Bioavailability & Bioequivalence

Effect of Food
 A required study – helps for dosage
administration in Clinical Trials Test Meal
 Measure PK parameters (rate and extent) under
2 eggs fried in butter
Fasted and Fed conditions.
2 strips of bacon
 Single dose cross over study is recommended.
2 slices of toast with butter
 FDA Guidance gives type of food
4 oz of hash-brown potatoes
High Fat Meal (breakfast) – total of 800 –
1000 calories 8 oz of whole milk
of which 150 cal from Proteins, 250 cal from
carbohydrates and 500 – 600 cal from fat.

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Bioavailability & Bioequivalence

Effect of Food on Rivastigmine Absorption

M E A N R IV A S T IG M IN E P L A S M A L E V E L S (n g /m L )
7

3 3 mg (fasted) N=20
3 mg (fed) N=19

-1
0 2 4 6 8 10 12 14
TIME (hrs)

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Bioavailability & Bioequivalence

Effect of Food on Lescol XL

Concentration (ng/mL) 150


Fasted
120 Fed
90

60

30

0
0 6 12 18 24
Time (h)

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Bioavailability & Bioequivalence

Food Effect
 Statistical analysis is done for significant difference

 PK data interpretations are made in conjunction with clinical experience /


clinical significance

 Attention should be paid for the absorption rate and total exposure with
and without food. Cases when time to peak concentration is important
(analgesic)

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Bioavailability & Bioequivalence

Summary
 Absorption is influenced by physico-chemical properties of the drug,
formulation factors, and the anatomy and physiologic functions at the site
of drug absorption.

 Drug absorption process may be zero order (active transport) or first


order (passive diffusion) process.

 Highly soluble and highly permeable drugs are rapidly absorbed.

 Estimation of drug absorption and bioavailability is critical in early stage


drug development.

 BE studies are required for changing formulations etc.

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Bioavailability & Bioequivalence

How Drug Metabolism


affects Bioavailability?

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Bioavailability & Bioequivalence

Drug metabolism/Biotransformation

Liver is the main site of drug metabolism

Extrahepatic:
Gut wall
Intestinal Flora
Lung
Kidney

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Bioavailability & Bioequivalence

Reactions Catalyzed by Drug metabolizing


enzymes

Oxidative reactions (Phase I)


dealkylation
hydroxylation
oxidation
Deamination

Conjugation reactions (Phase II)


glucuronidation
glutathione conjugation
sulfation
acetylation

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

How Drug Metabolism Affects Bioavailability?

 Genetic (polymorphism in expression of enzymes in


a population)
 CYP2D6, CYP2C19, NAT2, etc.
 Environmental (food, smoking)
 Grapefruit juice (↑AUC and ↑Cmax)

 Drug-Drug interaction
 Inhibition (↑AUC and ↑Cmax)
 Induction (↓AUC and ↓Cmax)

 Age
 Disease (hepatic impairment)

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

St. John’s Wort

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Bioavailability & Bioequivalence

How Transporters affect


Bioavailability?

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Energy Dependent Efflux Transporters –


ATP-binding cassette (ABC) proteins

Work against concentration gradient


 MDR1 (P-glycoprotein)
 MDR3
 MRP2 (multidrug resistance associated protein,
cMOAT)
 BSEP (bile salt export pump)
 BCRP (breast cancer resistance protein)

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Bioavailability & Bioequivalence

How Transporters Affect Bioavailability?

P-glycoproteins expressed in
 Intestine limit absorption  low BA
 liver  increase bile secretion  low BA
 kidney  increase secretion in urine  shorten t1/2
 Brain  protect CNS from penetration of toxic drugs
or decrease efficacy of CNS drugs
 Some lymphocytes  drug resistance for HIV drugs

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Bioavailability & Bioequivalence

Bioequivalence: Background
 Using bioequivalence as the basis for approving generic copies of drug
products was established by the “Drug Price Competition and Patent Term
Restoration Act of 1984,” also known as the Waxman-Hatch Act.

 This Act expedites the availability of less costly generic drugs by permitting
FDA to approve applications to market generic versions of brand-name drugs
without conducting costly and duplicative clinical trials. 

 At the same time, the brand-name companies can apply for up to five
additional years longer patent protection for the new medicines they
developed to make up for time lost while their products were going through
FDA's approval process. Brand-name drugs are subject to the same
bioequivalence tests as generics upon reformulation. 

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

Bioequivalence
Definition - CFR 320.1
It is the absence of significance difference in the rate and
extent to which active ingredient or active moiety in
pharmaceutical equivalent or pharmaceutical alternative
becomes available at the site of drug action when
administered at the same molar dose under similar conditions
in an appropriately designed study

Note: BE has a specific definition and regulatory


requirements. BE is not the same as the BA

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

When do we do BE studies ?

 Clinical Service Form to Final Market Form

 Change of formulations (capsules to tablet)

 Generic Formulations

 Change of Process or manufacturing site (some


times)

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

Bioequivalence

 Test Batch Size: 100,000 units or 10% of Production


size whichever is greater

 Retention Samples: Need to retain samples at the


study site for further analysis (5 times).

 Most of the BE studies are audited by HAs especially


for NMEs

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Bioavailability & Bioequivalence

Bio-IND

“The primary purpose of a Bio-IND is to ensure that the


proposed product is safe for use in human test subjects and
does not expose them to undue risk and untoward effects from
the drug product”
MAPP 5240.4, CDER, FDA

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Bioavailability & Bioequivalence

Contents of a Bio-IND

 OGD's new policy is that in addition to a protocol, sufficient


information must be submitted in a Bio-IND to enable an OGD
bioequivalence reviewer and a review chemist to determine the
safety of the formulation to be used in the proposed
bioequivalence study.

 Only one protocol per Bio-IND submission

 Components and composition of the generic drug to be used in


the bioequivalence study including the amounts of the active
ingredient(s) and excipients

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Bioavailability & Bioequivalence

Contents of a Bio-IND

 Tests and specifications for identity, strength, quality, and purity for
active ingredient(s) and Certificates of Analysis of excipients;
 Method and place of manufacturing including the type of equipment,
batch size and batch records
 Tests and specifications for the finished dosage form (Certificates of
Analysis);
 Stability testing data on the drug product stored for three months at
400C and 75% relative humidity including information on the
container/closure system(s) used in the stability tests unless other
conditions are appropriate for that product.

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Bioavailability & Bioequivalence

Filing and Review Procedures

 A Bio-IND received in the Document Room will be identified by its


cover letter and standard form 1571.
 The Bio-IND will then be routed to the central CSO staff which will
review the submission for acceptability and send out an
acknowledgment letter under the signature of the Director, OGD.
 If the Bio-IND does not contain the information described in POLICY
AND PROCEDURE, Contents of a Bio-IND, a refuse to file letter
will be issued and the firm will have to correct the deficiencies and
resubmit the Bio-IND.
 If a Bio-IND is determined to be acceptable for filing, the thirty-day
safety review clock will start on the date of receipt of the submission.

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Bioavailability & Bioequivalence

Filing and Review Procedures

 The central CSO staff will send


one copy to the appropriate OGD Chemistry Branch based upon the
pharmacological class of the drug to be studied
another copy to the Division of Bioequivalence or the appropriate
NDE reviewing Division, and
a third copy to the Document Room to be filed
 Normally, the Division of Bioequivalence will review the protocol
for the bioequivalence study to ensure that the safety of subjects
entering the study will not be compromised.
 If a protocol raises a medical issue such as proposing to
administer a dose not addressed in the labeling, a medical officer
in NDE will be consulted.

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Bioavailability & Bioequivalence

Filing and Review Procedures

 Information on chemistry, manufacturing, and controls will be


reviewed by one of the two Divisions of Chemistry to ensure the
safety of the study volunteers. A more detailed review will be
conducted of the chemistry, manufacturing and controls information
that is later submitted in the ANDA.

 A CSO will be assigned the responsibility to track the Bio-IND


through the review process, including checking periodically with the
reviewing divisions on the status of the reviews.

 If the CSO determines that the safety reviews will not be completed
within thirty days, he or she will inform the firm and may request
that the start of the study be deferred until the reviews are completed.

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Filing and Review Procedures

 Upon completion of the safety reviews, OGD will notify the firm that the
study may begin or that the study has been placed under a clinical hold
pursuant to 21 CFR § 312.42.

 The chemistry and bioequivalence reviews of the Bio-IND, when


completed, will be sent back to the central CSO staff. That staff will
prepare the appropriate action letter for the signature of the Director,
OGD.

 A bioequivalence study completed under a Bio-IND should be submitted


in the ANDA which it supports. No bioequivalence studies should be
submitted as amendments to Bio-IND's.

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Bioavailability & Bioequivalence

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Waivers of In Vivo Study


Requirements

 Criteria (21 CFR 320.22)


In vivo bioequivalence is self evident
Parenteral Solutions
Inhalation anesthetics
Topical skin solutions
Oral solutions
Different proportional strength of product with
demonstrated BE

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Bioavailability & Bioequivalence

The Biopharmaceutics Classification


System (BCS) Guidance

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Purpose of the BCS Guidance: 

 Expands the regulatory application of the BCS and recommends


methods for classifying drugs.

 Explains when a waiver for in vivo bioavailability and bioequivalence


studies may be requested based on the approach of BCS.

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Bioavailability & Bioequivalence

BCS Classifications

According to the BCS, drug substances are


classified as follows:

Class I - High Permeability, High Solubility


Class II - High Permeability, Low Solubility
Class III - Low Permeability, High Solubility
Class IV - Low Permeability, Low Solubility

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Bioavailability & Bioequivalence

CLASS BOUNDARIES

 A drug substance is considered HIGHLY SOLUBLE when the


highest dose strength is soluble in < 250 ml water over a pH
range of 1 to 7.5.
 A drug substance is considered HIGHLY PERMEABLE when
the extent of absorption in humans is determined to be > 90% of
an administered dose, based on mass-balance or in comparison to
an intravenous reference dose.
 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.

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Bioavailability & Bioequivalence

SOLUBILITY DETERMINATION

 pH-solubility profile of test drug in aqueous


media with a pH range of 1 to 7.5.

 Shake-flask or titration method.

 Analysis by a validated stability-indicating assay.

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Bioavailability & Bioequivalence

PERMEABILITY DETERMINATION

Extent of absorption in humans:


Mass-balance pharmacokinetic studies.
Absolute bioavailability studies.

Intestinal permeability methods:


In vivo intestinal perfusions studies in humans.
In vivo or in situ intestinal perfusion studies in animals.
In vitro permeation experiments with excised human or animal
intestinal tissue.
In vitro permeation experiments across epithelial cell monolayers.

Bioavailability & Bioequivalence, June 2, 2004


Bioavailability & Bioequivalence

Determining Drug Product Dissolution Characteristics and


Dissolution Profile Similarity

Dissolution testing should be carried out in USP Apparatus


I at 100 rpm or Apparatus II at 50 rpm using 900 ml of the
following dissolution media:
0.1N HCl or Simulated Gastric Fluid USP without enzymes
a pH 4.5 buffer
a pH 6.8 buffer or Simulated Intestinal Fluid USP without
enzymes

For capsules and tablets with gelatin coating


Simulated Gastric and Intestinal Fluids USP (with enzymes) can
be used.

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Bioavailability & Bioequivalence

Dissolution Profile Similarity


 A minimum of 12 dosage units of a drug product should be evaluated to
support a biowaiver request.
 Samples should be collected at a sufficient number of intervals to characterize
the dissolution profile of the drug product (e.g., 10, 15, 20, and 30 minutes).
 When comparing the test and reference products, dissolution profiles should
be compared using a similarity factor (f2). The similarity factor is a
logarithmic reciprocal square root transformation of the sum of squared error
and is a measurement of the similarity in the percent (%) of dissolution
between the two curves.
f2 = 50 * log {[1+(1/n)*t=1n (Rt - Tt)2]-0.5 * 100}

 Two dissolution profiles are considered similar when the f2 value is 50.
Note: When both test and reference products dissolve 85% or more of the label amount of the drug
in 15 minutes using all three dissolution media recommended above, the profile comparison with
an f2 test is unnecessary.

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Bioavailability & Bioequivalence

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

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Bioavailability & Bioequivalence

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

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Bioavailability & Bioequivalence

BCS Class I: Solubility

 Highest dose strength should be soluble in < 250 mL


Volume is derived from BE protocols
Doses are generally administered with about 8 oz water

 Determinations should use a range of pH values


over 1 to 7.5, a temperature of 370C, and
equilibrium conditions

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Bioavailability & Bioequivalence

BCS Class I: Permeability

 In vivo methods include determination absolute BA (>


90%) or mass balance
 In vitro intestinal permeability can be determined by
several methods
One method is use of cultured epithelial cell monolayers

 A single method may be sufficient


 Stability in GI tract should be determined

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Bioavailability & Bioequivalence

BCS Class I: Permeability

 For prodrugs, permeability depends on


mechanism, anatomical site of conversion
 When conversion occurs prior to intestinal
permeation, measure permeability of active
moiety
 When conversion occurs after intestinal
permeation, measure permeability of prodrug

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Bioavailability & Bioequivalence

BCS Class I: Excipients

 Quantity of excipients should be consistent with


intended function

 Large quantities of some surfactants may be


problematic
polysorbate 80
Mannitol
sorbitol

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Bioavailability & Bioequivalence

Recent Federal Register Notice

 FDA is proposing to amend its regulations to require an


ANDA applicant to submit data from all bioequivalence
studies (BE studies)
 In the past, ANDA applicants have not typically submitted
additional BE studies conducted on the same drug product
formulation, such as studies that do not show that the product
meets these criteria.
 FDA is proposing this change because the data from additional
BE studies may be important in determination of whether the
proposed formulation is bioequivalent to the RLD and are
relevant to evaluation of ANDAs in general.
 In addition, such data will increase understanding of how
changes in components, composition, and methods of
manufacture may affect formulation performance.

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Bioavailability & Bioequivalence

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Bioavailability & Bioequivalence

References

 Clinical Pharmacokinetics: Concepts and Application - 3rd


Edition
By Malcolm Rowland & Thomas N. Tozer

 http://www.fda.gov/cder/guidance/index.htm

 http://www.access.gpo.gov/nara/cfr/waisidx_03/21cfr320_03.ht
ml

Bioavailability & Bioequivalence, June 2, 2004

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