Lecture 1 the BCS From Theory to Applications in Product and Reg-01

8/18/2019 Lecture 1 the BCS From Theory to Applications in Product and Reg-01

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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





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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





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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!

Lecture 1 the BCS From Theory to Applications in Product and Reg-01

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