Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo...
Transcript of Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo...
![Page 1: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/1.jpg)
Drug combinations: quantifying synergistic or antagonistic
interactions
Vallo Varik
2017-11-17
![Page 2: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/2.jpg)
Introduction
![Page 3: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/3.jpg)
Interaction of two or more agents is important
Drug treatment
combinational therapies
inadvertent combinations
Environment
Toxicology
Yet missing in most pharmacology textbooks
![Page 4: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/4.jpg)
Terminology of the interaction can be a source of confusion in itself
Zero interaction, additivity, noninteraction, inertism, independence
Synergy, superadditivity, supra-additivity, potentiation, augmentation, coalism
Antagonism, subadditivity, depotentiation, negative interaction, negative synergy, infra-additivity
![Page 5: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/5.jpg)
In one very specifc case, the “expected” is easy to agree on
![Page 6: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/6.jpg)
Most common approaches
Efect based- Subthresholding
- HSA
- Sum
- Product (Bliss)
Dose based
- Isoboles (Loewe)
No method
Empirical
“By far the most often used... in which explicit criteria are conspicious by their absence”
Berenbaum 1989 Pharm Reviews
Saariselkä (Finland) agreement 1992
![Page 7: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/7.jpg)
Efect based approaches
![Page 8: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/8.jpg)
Subthresholding, if applicable, takes purely statistical approach
![Page 9: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/9.jpg)
HSA postulates that two drugs are expected to be only as good as the better one
![Page 10: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/10.jpg)
Response summation assumes that drugs act independently on the same target (site) and dose-response is linear
![Page 11: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/11.jpg)
Bliss independence assumes that the drugs act independently on diferent sites
![Page 12: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/12.jpg)
Most common criticism of efect based approaches: (1) impose a mechanism; (2) fail in sham combination test
Foucquier J & Guedj M 2015 Pharmacol Res Perspect
![Page 13: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/13.jpg)
Dose based approachLoewe isoboles
![Page 14: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/14.jpg)
What is isobole and how can I get one?
Tallarida RJ 2012 J Pharmacol Exp Ther
![Page 15: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/15.jpg)
What is isobole and how can I get one?
Tallarida RJ 2012 J Pharmacol Exp Ther
synergy
antagonism
![Page 16: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/16.jpg)
There is an isobole for every efect, not just 50%
Tallarida RJ 2007 Pharmacol Ther
![Page 17: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/17.jpg)
The synergy is not only about the dose and efect, it is also about the ratio of compounds
Berenbaum MC 1989 Pharmacol Rev
1:1
1:2
1:4
![Page 18: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/18.jpg)
What is the equation of the isobole line we just saw?Meet the notation
a – concentration of drug A
b – concentration of drug B
Eab – efect of the combination
A – concentration of drug A alone that gives efect Eab
B – concentration of drug B alone that gives efect Eab
![Page 19: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/19.jpg)
What is the equation of the isobole line we just saw?Derive the equation
So, dose additivity
b + a
The key concept, the trick, is to fnd isoefective, equivalent dose
b + b’
b + a × B/A = B
We actually wanted to have an equation for the isobole:
aA +
bB=1
b = B – a × B/A
![Page 20: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/20.jpg)
What did we just do when were adding the doses?
Tallarida RJ 2007 Pharmacol Ther
b’
![Page 21: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/21.jpg)
What is isobole and how can I get one?
Tallarida RJ 2012 J Pharmacol Exp Ther
b = B – a × B/A
b
a
![Page 22: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/22.jpg)
What about when the potency ratio is not fxed?
b'=EC b50
[E bmax
E amax
(1+EC a
q
50aq
)−1]1p
p – hill coefcient for Bq – hill coefcient for A
![Page 23: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/23.jpg)
Criticism of Loewe additivity
Linear isoboles are rarity
Often, no clear prediction can be generated
(1) if hill coefcients are diferent, b+b’ (P) and a+a’ (Q) give diferent isoboles
(2) Boundary conditions need some additional solutions if (i) one efect is very low, or (ii) if drug B has higher Emax (b’ is not readily available)
Tallarida RJ 2007 Pharmacol Ther
![Page 24: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/24.jpg)
Few additional, perhaps even most important take home thoughts
![Page 25: Drug combinations: quantifying synergistic or antagonistic ... · myPresentation Author: Vallo Varik Created Date: 11/20/2017 1:21:41 PM ...](https://reader030.fdocuments.us/reader030/viewer/2022041022/5ed27bfdc3bfbc34d61e9315/html5/thumbnails/25.jpg)
Therapeutic synergy and in vitro synergy are diferent things
Increased selectivity
Other, more important reasons for combinational therapy
“It may be useful to study the changes observed in a well-characterized, empiric combined action caused by changes in other variables (other drugs, cell lines, temperature, pH etc)”
Greco WR et al. 1996 J Natl cancer Inst