lecture 1 the bcs from theory to applications in product and reg-01
TRANSCRIPT
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BCS From Theory to
Applications in ProductDevelopment and Drug
Product RegulationGordon L. Amidon
College of Pharmacy
University of Michigan Ann Arbor, MI 48109-1065
Email: [email protected]
Amman, Jordan: September 23-24, 2013
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What is the Role of the
Pharmaceutical Scientist?Deliver High PharmaceuticalQuality Product to the patient
The product performs
according to the labelclaims.
How good are label
claims?
PharmaceuticalStandards!
How do we set them?
What is highPharmaceutical Quality?
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Why is BE Important?
BE connects the product in the
bottle with the claims on the
label! Label
Product
“BE”
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Biopharmaceut ics
Class Solubi l i ty Permeabi l i ty
I High High
II Low High
III High Low
IV Low Low
FDA BCS Guidance
BCS Class I Biowaivers
BCS Class III BiowaiversRecommended and
Under Consideration
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Systemic (BA) vs. Oral Transport
View (BE)
The
Science of
BE is at the
AbsorptionSite
BA
BE
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Flux = eff j P C
BCS takes a mechanistic approach to
setting bioequivalence standards: Mass
Transport in the GI Tract
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First Principle of
Bioequivalence
If a drug from two productsare presented to the Intestinal
Surface Equivently they will be
Bioequivalent
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Diffusion vs. Pharmacokinetic
Views of Absorption
( / )1/
/sec.
J dM dt A
P C P C
P cm
Diffusion Pharmacokinetic
Software e.g. GastroPlus®
( / )a eff k S V P
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Absorption Rate Coefficient:
ka ~Local Permeability(Peff)Transport
(1/ )( / )
PK
/ (1/ ) /
Permeability ~ Absorption Rate Coefficient(constant)
Equating dM/dt : A
( / )
(2 / )
2 (1.75)
~
Numerically (Units
eff
a
eff a
a eff
a eff eff
a eff
J A dM dt P C
dC dt V dM dt k C
P C V k C
k A V P
k R P P
R cm
k P
differ: 1/sec vs. cm/sec)
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Flux = eff j P C
BCS takes a mechanistic approach to
setting bioequivalence standards: Mass
Transport in the GI Tract
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Biopharmaceutics Classification
System (BCS): Basis
0
)M(t) ( eff
t
A
C P dAdt
Absorption per unit area per unit
time
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Why is BE Important?
BE connects the product in the
bottle with the claims on the
label! Label
Product
“BE”
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Bioequivalence (BE) Today
Historically a Relative Bioavailability (BA)Based View
– Misses the underlying scientific issues
IN Vivo Dissolution
BE Testing is Same Drug
– Once Absorbed PK is the Same
The Science of BE is at the AbsorptionSite
– For Oral Dosage Form in the GI Tract
The Question is: What is the Best BE Test
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Systemic (BA) vs. Gut View (BE)
The
Science of
BE is at the
AbsorptionSite
BA
BE
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BCS t k h i ti h t
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Flux = eff j P C
BCS takes a mechanistic approach to
setting bioequivalence standards: Mass
Transport in the GI Tract
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August 2000 FDA Guidance
G.L. Amidon et. al., Pharmaceutical Research, 12,
413 (1995).
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EMEA/CPMP and FDA/BCS
FDA/BCS EMA/CPMP WHO BE
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FDA/BCS, EMA/CPMP, WHO BE
Recommendations
(2000-2010)
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Annex 7 page 347
Annex 8 page 391
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FRAMEWORK FOR IMPLEMENTATION OF
EQUIVALENCE REQUIREMENTS FOR
PHARMACEUTICAL PRODUCTS
Document for Public Opinion
WORKING GROUP ON BE
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What is the BCS? Permeability
and Solubility Classification
Biopharmaceut ics
ClassSolubi l i ty Permeabi l i ty
I High High
II Low High
III High Low
IV Low Low
The BCS is a scientific framework for classifying drugs
based on their aqueous solubility and intestinal
permeability and setting the best Bioequivalence
Test.
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Maximum Flux (Absorption)
max/ (1/ )
Mass Absorbed per Unit Time per Unit AreaC Solubility
eff s
s
dM dt A J P C
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High Solubility Drug
Vs = Volume of Solution
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Diffusion vs. Pharmacokinetic
Views of Absorption
( / )1/
/sec.
J dM dt A
P C P C
P cm
Diffusion Pharmacokinetic
Software e.g. GastroPlus®
( / )a eff S V k P
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Human Permeability
N. Takamatsu, et al. Pharm.Res., 14, 1127 (1997).
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Human Jejunal Permeability(The ‘Gold’ Standard)
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Fabs vs.Peff (cm/sec)(Human Jejunum)
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Human jejunum permeability (x10-4
cm/s)
0 2 4 6 8 10 12
H
umanfractionabsorbed(%)
0
20
40
60
80
100
120
Trend line
D-glucose
Verapamil
Piroxicam
Phenylalanine
Cyclosporin
Enalapril
Cephalexin
LosartanLisinopril
Amoxicillin
Methyldopa
Naproxen
Antipyrine
Desipramine
Propanolol
Amiloride
Metoprolol
Terbutaline
Mannitol
Cimetidine
Ranitidine
Enalaprilate
Atenolol
Hydrochlorothiazide
Human Fraction Absorbed vs. Jejunal
Permeability pH=6.5
Sun et.al Pharm. Res. 19, 1400, 2002
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Human Permeability
N. Takamatsu, et al. Pharm.Res., 14, 1127 (1997).
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Tissue Culture Permeability
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0.01
0.1
1
10
0.01 0.1 1 10 100 1000
Caco-2 permeability (x 10-6
cm/s) at pH 6.5
H u m a n
j e j u n u m
p e r m e a b i l i t y ( x 1 0 - 4
c m / s ) a t p H 6 . 5
Furosemide
Hydrochlorothiazide
Atenolol
Cimetidine
Mannitol
Terbutaline
Amoxicillin (C)
Lisinopril(C)
Metoprolol
Cephalexin (C)
Enalapril (C)
Propranolol
Phenylalanine (C)
Desipramine
Antipyrine
Piroxicam
Verapamil (C)
Ketoprofen
Naproxen
D-Glucose (C)
logY = 0.6532 logX - 0.3036, R 2 = 0 .7276 (all drugs)
logY = 0.7524 logX - 0.5441, R 2 = 0 .8492 (passive diffusive drugs)
Human Caco-2 Permeability
Correlation
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‘In Silico’ (Computational)
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Drug database of oral immediate-release (IR)
drugs on 200 top-selling US, GB, ES, JP, and KR
drug products
US: 113 oral IR drugs (56.5%)
GB: 102 oral drugs (51.0%)
ES: 106 oral drugs (53.0%)
JP: 113 oral drugs (56.5%)
KR: 87 oral drugs (43.5%)
Based on 200 top-selling drug products in 5 countries, and WHOEssential drugs, drug databases of Combined List (346 drugs),Western List (147 drugs), Eastern List (163 drugs) was made andanalyzed on molecular properties and BCS classification.
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Comparison of the provisional BCS classification of in silico vs.
referenced solubility approaches on 185 oral IR drugs
0.0
5.0
10.0
15.0
20.025.0
30.0
35.0
40.0
45.0
50.0
based on In
Silico
Solubility
based on
Referenced
Solubility
based on In
Silico
Solubility
based on
Referenced
Solubility
based on In
Silico
Solubility
based on
Referenced
Solubility
based on In
Silico
Solubility
based on
Referenced
Solubility
BCS Class 1 BCS Class 2 BCS Class 3 BCS Class 4
P e r c e n t a g e o f
o r a l I R
d r u g s
CLog P (BioLoom 5.0) and exp. M.P.
CLog P (BioLoom 5.0) and average M.P.CLog P (ChemDraw 8.0) and exp. M.P.
Log P (MOE 2004.03) and exp. M.P.
KLog P (Molecular Formula) and exp. M.P.
KLog P (Molecular Formula) and average M.P.
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BCS and Dissolution: The
FutureOral BE is a scientific question of in
vivo Dissolution
The in vivo Dissolution System
(Gastrointestinal Tract) is complex
We need to establish in vitro
Dissolution Systems
Need to Develop: Bioperformance
Dissolution Methods (BDM)
BE Dissolution Proposal (Starting
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BE Dissolution Proposal (Starting
Point)
BCS Class
Drug Solubility pH
1.2
Drug Solubility pH
6.8
Drug
Permeability Preferred Procedure
I High High High >85% Dissolution in 15 min; 30 min, f2., pH = 6.8.
II-A Low High High
15 min at pH=1.2, then 85% Dissolution in 30 min.,
pH = 6.8; F2>50; 5 points minimum; not more than
one point > 85%.
II-B High Low High >85% Dissolution in 15 min., pH = 1.2.
II-C Low Low High
15 min at pH=1.2; then 85% Dissolution in 30 min.,
pH = 6.8 plus surfactant*; F2>50; 5 points minimum,
not more than one point > 85%.
III High High Low >85% Dissolution in 15 min., pH = 1.2, 4.5, 6.8.
IV-A Low High Low15 min. at pH = 1.2; then 85% Dissolution in 30 min.,pH = 6.8,; F2>50; 5 points minimum.; not more than
one point > 85%.
IV-B High Low Low >85% Dissolution in 15 min., pH = 1.2.
IV-C Low Low Low
15 min at pH=1.2; then 85% Dissolution in 30 min.,
pH = 6.8 plus surfactant*; F2>50; 5 points minimum,
not more than one point > 85%.
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BCS Dissolution Proposal
This is too much to digest in one seminar
The USP can not do this because of it’s
charter
The FDA can not do this because of the
legal basis for proprietary information
This is how we do business (develop
products)
BCS d Di l ti
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BCS and Dissolution
ConclusionsNew BE ParadigmReduce Unnecessary In Vivo Studies
Increase Oral Product Quality
Based on Scientific Principles and Extendable – E.g. Food Effects
It is up to us!