The Biopharmaceutics Classification

System (BCS): From Theory to

Application to Product Development
Gordon L. Amidon
College of Pharmacy
University of Michigan
A A
Ann
Arbor,
b MI 48109
48109-1065
1065
Email: glamidon@umich.edu
Rhodes University, Dec 9-10, 2009

BE connects the product in the

bottle with the claims on the label!
Label

BE

Product

First Principle (Central Dogma) of

Bioequivalence: Oral Drugs
Systemically Active
Similar Plasma levels
Similar Pharmacodymanics
This was BE < 2000 (before
BCS Guidance)

August 2000 FDA Guidance

G.L. Amidon et.al., Pharmaceutical Research, 12,

413 (1995).

First Principle (Central Dogma) of

Bioequivalence: Oral Drugs
Systemically Active
Similar Plasma levels Similar
Pharmacodymanics
Similar In Vivo Dissolution Similar
Plasma Levels
In Vitro Dissolution In Vivo Dissolution

Bioequivalence
Critical Specification for Maintaining Drug
Product Efficacy over Time
Therapeutic Equivalence

The Question is: What is the Best Test?

BE
Plasma Paradigm vs. Mechanism

Biowaiver
Waiver of In Vivo BE
Studies--Not waiver of BE!

BCS takes a mechanistic approach to setting

bioequivalence standards: Mass Transport in
the GI Tract

Flux = j = Peff C

Bioequivalence (BE) Today

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
Th S
Science
i
off BE is
i att the
th Absorption
Ab
ti Site
Sit
For Oral Dosage Form in the GI Tract

The Question is: What is the Best BE Test

August 2000 FDA Guidance

G.L. Amidon et. al., Pharmaceutical Research, 12,

413 (1995).

EMEA/CPMP and FDA/BCS

FDA and CPMP Biowaivers

High
g So
Solubility
ub ty ppH 1-7.5
7.5
(6.8)
High Permeability(HP)
=(Fabs>90%)
Rapid Dissolution T85
<30 min., pH= 1.2,4.5, 6.8
Excipients currently
approved for IR Dosage
Forms (FDA Inactive
Ingredients List)
Non NTI Drugs

High
g So
Solubility,
ub ty, ppH 1-7.5
7.5
Linear and Complete
Absorption
Rapid Dissolution T85
<30 min, pH=1.0,4.6,6.8)
Excipients well
established (not large
doses)
Risk of Therapeutic
Failure Low

Annex 7
Annex 8

page 347
page 391

WHO (BE) Recommendations

Solubility and Permeability
Same as (~)FDA and EMEA
Dissolution and solubility pH=6.8 (rather than 7.5)

Dissolution: Very Rapid, Rapid, Not Rapid

Recommends Classes for drugs
g on (WHO)
(
)
EML
Recommends dissolution Biowaivers for
Class I, III, and some Class II Drugs

FRAMEWORK FOR IMPLEMENTATION OF

EQUIVALENCE REQUIREMENTS FOR
PHARMACEUTICAL PRODUCTS
Document for Public Opinion
WORKING GROUP ON BE

Oral Drug Absorption

J=Peff*Cs

10

Mass Transport
C / t + v C =
D 2C + R
BC : jw = DC / t = Peff C
IC : C = 0 (x, y, z) tube at, t = 0

Amidon, Lee and Topp Transport Processes in

Pharamceutical Systems, Dekker, NY, 2000 p 27ff

11

Biopharmaceutics Classification
System (BCS): Basis
t

M(t) = (Peff C)dAdt

0A

Absorption per unit area per unit time

Diffusion vs.Pharmacokinetic Views of

Absorption: A Simpler Well Mixed
View
Diffusion

J = (dM / dt )1/ A
= P C P C
P = cm / sec.

Pharmacokinetic
dC / dt = (dM / dt )1/ V
= ka C ka C
ka = 1/ sec

k a = ( S / V ) Pe f f
Software e.g GastroPlus

12

Absorption Rate Coefficient: ka

Transport
J = (1/ A)(dM / dt ) = Peff C
PK
dC / dt = (1/ V )dM / dt = ka C
ka ~ Peff
ka = ( A / V ) Peff
ka = (2 / R) Peff Peff

BCS Basis
Drug is absorbed through the intestinal membrane
at a rate that is proportional to the concentration at
the membrane surface. The dissolution of the drug
product in vivo determines the membrane surface
concentration of drug.

Similar In Vivo Dissolution Similar In Vivo

Absorption Similar Systemic Availability (BE)

13

Bioequivalence (BE) is a Question

of Dissolution and Absorption
A BE In Vitro Dissolution Methodology
must capture the most important rate
controlling in vivo dissolution process

J=Peff*Cs

14

The Biopharmaceutics Classification

System (BCS)
J = (1 / A) dM / dt = Peff C
J max = Peff Cs
Cs = Solubilityy
G.L. Amidon, H. Lennernas, V.P Shah and J.R. Crison, A theoretical basis for a
biopharmaceutic drug classification: the correlation of in vitro drug product dissolution
and in vivo bioavailability, Pharm. Res., 12, 413 (1995).

What is the BCS? Permeability and

Solubility Classification
The BCS is a scientific framework for classifying drugs
based on their aqueous solubility and intestinal
permeability and setting the best Bioequivalence Test.
Biopharmaceutics
Class

Solubility

Permeability

High

High

II

L
Low

Hi h
High

III

High

Low

IV

Low

Low

15

How to Define Solubility and

Permeability Reference Values?

High Solubility Drug

FDA Glass of Water= 8 oz.
(240 ml)

V
Vs = V
Volume
l
off S
Solution
l ti
<250 ml,
pH=1-7.5
Highest Dose Strength
Do=Dose/250/C s <1

16

Human Permeability

N. Takamatsu, et al. Pharm.Res., 14, 1127 (1997).

Human Fraction Absorbed vs. Jejunal

Permeability pH=6.5
120

Huma
an fraction absorbed (%)

100

80

60

40

20

0
0

-4
Human jejunum permeability (x10 cm/s)

10

12

D-glucose
Verapamil
Piroxicam
Phenylalanine
Cyclosporin
Enalapril
Cephalexin
Losartan
Lisinopril
Amoxicillin
Methyldopa
Naproxen
Antipyrine
Desipramine
Propanolol
Amiloride
Mt
Metoprolol
l l
Terbutaline
Mannitol
Cimetidine
Ranitidine
Enalaprilate
Atenolol
Hydrochlorothiazide
Trend line

Sun et.al Pharm. Res. 19, 1400, 2002

17

Human Jenunal Permeabilities

Tissue Culture Permeability

18

Human Caco-2 Permeability

Correlation
10

Furosemide
Atenolol
Cimetidine
Mannitol
Terbutaline

Amoxicillin (C)

-4

Human jejun
num permeability (x 10 cm/s) at pH 6.5

Hydrochlorothiazide

Lisinopril(C)
Metoprolol
Cephalexin (C)
Enalapril (C)
Propranolol
Phenylalanine (C)

0.1

Desipramine
Antipyrine
Piroxicam
Verapamil (C)

logY = 0.6532 logX - 0.3036, R = 0.7276 (all drugs)

2
logY = 0.7524 logX - 0.5441, R = 0.8492 (passive diffusive drugs)

0.01
0.01

Ketoprofen
Naproxen

0.1

10

100

1000

D-Glucose (C)

-6

Caco-2 permeability (x 10 cm/s) at pH 6.5

Metoprolol Absorption

19

Dissolution and Gastric Emptying?

Gastric Emptying(Fed)

Kelly, Am. J. Physiol. 239, G71, 1980.

20

Gastric Emptying Limited

Absorption
Gastric Emptying Time for 50% Fluid Emptying, T50: Human

80
50 ml.
200 ml
60

T50 min

High Peff =>

Absorption Half-time
is Short
Gastric Emptying Rate
The Slow Step in the
Absorption Process
T50 ~ 15 min

40

20

0
I

II

III

Average

Gastric Motility Phase

Oberle, R, et.al. Gastroenterology,

99, 1275 (1990)

21

FDA and EMEA Guidances

Waivers of In Vivo BE Based on

BCS: Class I (Soluble) Drugs

85% Dissolution in 15 min: Single Point

85% Dissolution in 30 min: 3 points, f2
3 pHs ( USP SGF, SIF, and pH=4.5
Waive In Vivo BE!

22

Example: Propranolol
Permeability (Human) = 1.8x10
1 8x10-4 cm/sec
High (Experimental)
Solubility = 2 mg/ml pH < 7.5
Vs =180/2 = 90 ml (< 250 ml): High
High Solubility, High Permeability
Rapidly Dissolving
Class I : In Vitro Dissolution Standard
for BE

BE Dissolution Proposal
Drug Solubility
pH 1.2

Drug Solubility
pH 6.8

Drug
Permeability

High

High

High

II-A

Low

High

High

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

Low

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%.

IV-B

High

Low

Low

>85% Dissolution in 15 min., pH = 1.2.

IV-C

Low

Low

Low

BCS
Class

Preferred Procedure
>85% Dissolution in 15 min; 30 min, f2., pH =
6.8.
15 min at pH=1.2, then 85% Dissolution in 30
min pH = 6.8;
min.,
6 8; F2>50; 5 points minimum; not
more than one point > 85%.

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%.

23

BCS and Dissolution

Conclusions

New BE Paradigm
Reduce Unnecessary In Vivo Studies
Increase Oral Product Quality
Based on Scientific Principles and Extendable
E.g. Food Effects

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BCS Class Inferences

Solubility

Permeability

Absorption Rate

High

High

Well absorbed drugs. Controlled by

Gastric Emptying for rapidly dissolving
drug products. Cmax is the critical in vivo
parameter*.

Low

High

Drug may be well absorbed. Controlled by

Dissolution. Cmax is the critical in vivo
parameter*.

Hi h
High

L
Low

Limited oral absorption. Controlled by

P
Permeability.
bilit Cmax and
d AUC critical
iti l in
i
vivo parameters.

Low

Low

Poorly absorbed. Cmax and AUC critical in

vivo parameters.

*Since high permeability drugs are rapidly absorbed, maximum plasma concentrations (Cmax),
are indicative of overall AUC and long-duration in vivo studies are not required

FDA and CPMP Biowaivers

High
g So
Solubility
ub ty ppH 1-7.5
7.5
(6.8)
High Permeability(HP)
=(Fabs>90%)
Rapid Dissolution T85
<30 min., pH= 1.2,4.5, 6.8
Excipients currently
approved for IR Dosage
Forms (FDA Inactive
Ingredients List)
Non NTI Drugs

High
g So
Solubility,
ub ty, ppH 1-7.5
7.5
Linear and Complete
Absorption
Rapid Dissolution T85
<30 min, pH=1.0,4.6,6.8)
Excipients well
established (not large
doses)
Risk of Therapeutic
Failure Low

25