t.c. chou's sample slides for combo illustrations 4.23

8/13/2019 T.C. Chou's Sample Slides for Combo Illustrations 4.23

1/29

T.C. ChouT.C. Chou s Sample Slides fors Sample Slides forCombo IllustrationsCombo Illustrations

Theoretical Basis & References Theoretical Basis & ReferencesExperimental DesignExperimental Design

Algorithms for Computer Simulation Algorithms for Computer Simulation

Diagnostic PlotsDiagnostic PlotsInterpretation of DataInterpretation of Data

Presentation of DataPresentation of DataScope of Combination AnalysisScope of Combination AnalysisEcono Green BioEcono Green Bio --ResearchResearch


2/29

2

SynergismSynergism is more than Additive Effectis more than Additive Effect

AntagonismAntagonism

What isWhat is Additive EffectAdditive Effect ??

is less than Additive Effectis less than Additive Effect


3/29

IfIf II11 andand II22 each inhibitseach inhibits 30%30% of a bioof a bio --system, then in combination,system, then in combination, if additiveif additive

(i.e., no synergism nor antagonism)(i.e., no synergism nor antagonism)should inhibit:should inhibit:A.A. 60%60%

B.B.


4/29

4

Why Determination of Synergism is More Complicated than ExpectedWhy Determination of Synergism is More Complicated than Expected ::

An Example for Illustration :

We need bothPotency (D m) and Shape (m)

Not only Potency.


5/29

5

A Constant-Ratio Experimental Design Showing theOutlay of Two Drugs for Drug Combination Analysis


6/29

6

The Unified TheoryThe Unified TheoryDerivation of Major Biochemical and Biophysical Equations from the Median-Effect Equation

f a f u

= ( )DDm mThe Median-Effect Equation

Chou, J. Theor. Biol. 59: 253-276, 1976

f a /(1 f a ) = ( D / D m)m

log [( f a /(1 f a)] = m[log( D ) log D m]

log [( f a)1 1]1 = m log( D ) m log D m

f a /f u = D / D m

Michaelis-Menten equation

v/V max = [1+(K m /S)] 1

Hill equation

log [v/(V max v)] = n log(S) log (K)

Scatchard equation

[L] b = n[M] t [L] b[L] f Kd Kd

f a = [1+( D m / D )m ]1 f a = [1+( D m / D )m ]1

log [( f a /(1 f a)] = m[log( D ) log D m]

log [( f a)1 1]1 = m log( D ) m log D m

f a /f u = D / D m

Henderson-Hasselbalch equation

log [ H + ] = log K a + log[HA]

[A ]

pH = p K a + log[A]

[HA]

[Chou T.C. Pharmacol. Rev. 58: 621-681, 2006 ]


7/29

7

[Chou T.C. J. Theor. Biol. 59: 253-276, 1976 ]

a b

(Chou plot)


8/29

m = 1, 3, 5; D m = 1 m = 1; D m = 0.5 , 1, 2, 4, 6, 8, 16

The Dose-Effect Curve:

The Median-Effect Plot: (Chou Plot)

Median As the Universal Reference Point and Common Link

CompuSyn generated dose-effect curves with their corresponding median-effect plots, based on the

median-effect equation. CompuSyn software has been used. Draw A Specific Dose-Effect Curve

with A Minimum of Only Two Data Points If Reasonably Accurately determined .

Features: Efficiency, Economy, and Quantitative for Computer Simulation. 8


9/29

9

(Chou)

(Chou-Talalay)

(Chou and Chou)


10/29

10

AlgorithmAlgorithm for Computerized Simulation of Synergism,for Computerized Simulation of Synergism,

Additivism and Antagonism of the Effect of Multiple DrugsAdditivism and Antagonism of the Effect of Multiple Drugs

The Median Effect Equation(1) f a /f u = ( D / D m)m

(2) Log( f a /f u) = mlog( D ) mlog( D m)(3) f a = 1/[1+( D m / D )m]

(4) D x = D m[ f a /(1 f a )]1/m

( D x)1,2 = ( D )1+ ( D )2and ( D )1 /( D )2 = P/Q

D = Dose f a = fraction affected f u = fraction unaffected D m = median-effect dose

m = slope, Hill-type coefficientor kinetic order

(5) CI = ( D )1 + ( D )2 = 1 + 1( D x)1 ( D x)2 ( DRI )1 ( DRI )2

CI : Combination IndexCI = 1 (summation)

< 1 (synergism)> 1 (antagonism)

DRI : Dose-Reduction Index

( DRI )1 =( D x)1 , ( DRI )

2= ( D x)2

( D )1 ( D )2

For n Drug Combinations:

CI = ( D ) j( D x) j n

J =1

(4) D x = D m[ f a /(1 f a )]1/m

( D )1 = ( D x)1,2 x P/(P+Q)( D )2 = ( D x)1,2 x Q/(P+Q)

(5) CI = ( D )1 + ( D )2 = 1 + 1( D x)1 ( D x)2 ( DRI )1 ( DRI )2


11/29


12/29


13/29

(Chou-Chou Plot)

(Chou-Martin Plot)

13

Diagnostic PlotsCI < 1, Synergism

CI = 1, Additive

CI > 1, Antagonism

DRI > 1Reduced dose

Reduce Toxicity


14/29

14

How Much Synergy Is Synergism?How Much Synergy Is Synergism?


15/29

15


16/29

16


17/29

17


18/29

49 (11): 2059-2080, 2008

18


19/29

Comparison of Two-Drug Combinations for Anti-Cancer Agents

[Using Econo-Green Small Size Experimentation]In Vitro In Animal In Clinic (I)

Time & Effort 1-2 weeks 1-2 months 6 months~1 year

Non-wage Cost $200[cells and chemicals]

$3,000[nude mice]

Expensive Trials[Vary]

Sample Size > 2 x 10 6[cells]

> 65

[nude mice][Chou-Talalay method]

> 36[vary]

[Chou-Talalay Method]

QuantitativeSynergy

Determination

Very Easy[But frequently not

done properly

in the past]

Not So Difficult[Rarely properly done

in the past]

DifficultUse Surrogate Markers

and Fractional Doses


20/29

Two AntiTwo Anti --HIV Clinical TrialsHIV Clinical TrialsAZT + 3TCAZT + 3TCAuthorsAuthors J.J. Eron et al. (9 authors +

Northern Am. HIV Working Party

AZT + INFAZT + INF D. Mildvan et al. (21 authors)

N. Engl. J. Med. 333: 1662-1669, 1995PublicationPublication Antiviral Therapy 1(2): 77-88, 1996

28.5JournalJournalImpact FactorImpact Factor

3.1

Number of PatientsNumber of Patients

Surrogate MarkerSurrogate Marker

What TheyWhat TheyHave ProvedHave Proved

366 36CD 4+ , HIV-RNA P24 Antigen, CD 4+

Combination Effect is Greater

than Each Drug AloneNot Possible to Claim Synergism

A+B > A, A+B > B (p


21/29

Exp. Design &Table Formfor ResultsReport (I & II)

Also Shown are theExperimental

Designs for Two- orThree- Drug

Combinations

21


22/29

22


23/29

23

Two Drug Combinations for Seven AntiTwo Drug Combinations for Seven Anti --HIV Agents and theHIV Agents and theHeptagonalHeptagonal PolygonogramsPolygonograms for Cocktail Designfor Cocktail Design


24/29

24

5-Drug

PolygonogramWith 5 Different

Mechanisms

Mechanisms CanNot Predict

Synergy !

PolygonogramProjects Outcome

Visually andSemi-quantitatively


25/29

25

Computerized Simulation ofComputerized Simulation of

Synergism/AntagonismSynergism/AntagonismPrimary Questions:Primary Questions:

Are there any synergism?Are there any synergism?

How much synergism?How much synergism?

Synergism at what dose levels?Synergism at what dose levels?

Synergism at what effect levels?Synergism at what effect levels?

What the exhibited isobologram looks like?What the exhibited isobologram looks like?How many folds dose reduction for each drugHow many folds dose reduction for each drug

as results of synergism?as results of synergism?

Other Questions:Other Questions:Optimal combination ratioOptimal combination ratio

Schedule dependencySchedule dependency

Selectivity of synergismSelectivity of synergism

Condition directed synergismCondition directed synergism

[[The Practical & Quantitative BioThe Practical & Quantitative Bio --InformaticsInformatics ]]


26/29


27/29


28/29


29/29

29

t.c. chou's sample slides for combo illustrations 4.23

Documents