frequency-domain response analysis for quantitative systems pharmacology models
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Frequency-domain response analysis for quantitativesystems pharmacology modelsNovember 17, 2016
Pascal Schulthess
Systems PharmacologyLeiden Academic Centre for Drug Research (LACDR)Leiden University, The Netherlands
I’m an Control Engineer.
with a PhD in Theoretical Biophysics.now doing a PostDoc in Mathematical Pharmacology.
1
I’m an Control Engineer
.
with a PhD in Theoretical Biophysics.
now doing a PostDoc in Mathematical Pharmacology.
1
I’m an Control Engineer
.
with a PhD in Theoretical Biophysics
.
now doing a PostDoc in Mathematical Pharmacology.
1
A short excursion intoengineering
Mass-spring-damper system with base excitation
u
y
2
Mass-spring-damper system with base excitation
u
y
2
Mass-spring-damper system with base excitation
u
y
2
Mass-spring-damper system with base excitation
u
y
2
Mass-spring-damper system with base excitation
u
y
2
Mass-spring-damper system with base excitation
u
y
2
Mass-spring-damper system with base excitation
u
y
2
Frequency-domain response analysis
• How does a system respond to periodic inputs?
• Which input frequencies amplify/attenuate the output?
• Is there resonance?
3
Frequency-domain response analysis
• How does a system respond to periodic inputs?
• Which input frequencies amplify/attenuate the output?
• Is there resonance?
3
Frequency-domain response analysis
• How does a system respond to periodic inputs?
• Which input frequencies amplify/attenuate the output?
• Is there resonance?
3
Where’s the connection to pharmacology?
3
FdRA for QSP models
A tolerance and rebound PD model
4
A tolerance and rebound PD model
x1
u
x2
kin kout
ktol ktol
4
Response characteristic of the PD model
x1
u
x2
kin kout
ktol ktol
5
Response characteristic of the PD model
u G y
5
Response characteristic of the PD model
u G y
5
Response characteristic of the PD model
u G y
Input
u(t) = sin(ωt)
5
Response characteristic of the PD model
u G y
Input
u(t) = sin(ωt)
Output
y(t) = Asin(ωt+ φ)
5
Response characteristic of the PD model
u G y
Input
u(t) = sin(ωt)
Output
y(t) = Asin(ωt+ φ)
5
Frequency response of the PD model
x1
u
x2
kin kout
ktol ktol
Model equations
x(t) =[0 −koutktol −ktol
]x(t) +
[kin0
]u(t)
y(t) =[1 0
]x(t)
6
Frequency response of the PD model
Model equations
x(t) =[0 −koutktol −ktol
]x(t) +
[kin0
]u(t)
y(t) =[1 0
]x(t)
Transfer function
G(iω) =[1 0
] ([iω 00 iω
]−
[0 −koutktol −ktol
])−1 [kin0
]
=kin(ktol − iω)
ω2 − ktol(kout − iω)
6
Frequency response of the PD model
Model equations
x(t) =[0 −koutktol −ktol
]x(t) +
[kin0
]u(t)
y(t) =[1 0
]x(t)
Transfer function
G(iω) =[1 0
] ([iω 00 iω
]−
[0 −koutktol −ktol
])−1 [kin0
]=
kin(ktol − iω)
ω2 − ktol(kout − iω)
6
Frequency response of the PD model
Transfer function
G(iω) =[1 0
] ([iω 00 iω
]−
[0 −koutktol −ktol
])−1 [kin0
]=
kin(ktol − iω)
ω2 − ktol(kout − iω)
Magnitude
A = |G(iω)|
Phase shift
φ = argG(iω)
6
Frequency response of the PD model
Transfer function
G(iω) =kin(ktol − iω)
ω2 − ktol(kout − iω)
Magnitude
A = |G(iω)|
Phase shift
φ = argG(iω)
6
Alternative treatment scheme to optimise effect amplitude
7
Alternative treatment scheme to optimise effect amplitude
ResultTreatment every 8 hours minimises effect amplitude.
7
Alternative treatment scheme to optimise effect amplitude
ResultTreatment every 24 hours maximises effect amplitude.
7
FdRA allows for
analyticaloptimisation of dosing frequency.
7
Influence of model parameters
8
Influence of model parameters
8
Influence of model parameters
8
FdRA highlights how
parametersinfluence treatment scheme.
8
Potential of FdRA in QSP
Frequency Dependence of Osmo-Adaptation in yeast
Mettetal et al., Science (2008) & Muzzey et al., Cell (2009) 9
Frequency Dependence of Osmo-Adaptation in yeast
Mettetal et al., Science (2008) & Muzzey et al., Cell (2009) 9
Frequency dependence of osmo-adaptation in yeast
Mettetal et al., Science (2008) & Muzzey et al., Cell (2009) 10
Frequency dependence of osmo-adaptation in yeast
Mettetal et al., Science (2008) & Muzzey et al., Cell (2009) 10
Frequency dependence of osmo-adaptation in yeast
− Mapk signalling& nuclear import
Hog1-independentmechanisms
Hog1-dependentmechanisms
+
Glycerolaccumulation
Osmext Hog1∗
Osmint
Mettetal et al., Science (2008) & Muzzey et al., Cell (2009) 10
FdRA enables
model identificationfrom experiments.
10
Conclusion & outlook
Conclusion
Frequency-domain response analysis
• allows for analytical dosing frequency optimisation
• highlights how parameters influence treatment scheme
• enables model identification from experiments
11
Conclusion
Frequency-domain response analysis
• allows for analytical dosing frequency optimisation
• highlights how parameters influence treatment scheme
• enables model identification from experiments
11
Conclusion
Frequency-domain response analysis
• allows for analytical dosing frequency optimisation
• highlights how parameters influence treatment scheme
• enables model identification from experiments
11
Conclusion
Frequency-domain response analysis
• allows for analytical dosing frequency optimisation
• highlights how parameters influence treatment scheme
• enables model identification from experiments
11
Outlook
Open questions
• Which systems give rise to which response behaviour?
• Can FdRA identify model structures from experiments?
• Is FdRA able to suggest (better) treatment schedules?
• Can FdRA be extended to allow combinatory treatments?
• How to incorporate FdRA into clinical practice?
12
Outlook
Open questions
• Which systems give rise to which response behaviour?
• Can FdRA identify model structures from experiments?
• Is FdRA able to suggest (better) treatment schedules?
• Can FdRA be extended to allow combinatory treatments?
• How to incorporate FdRA into clinical practice?
12
Outlook
Open questions
• Which systems give rise to which response behaviour?
• Can FdRA identify model structures from experiments?
• Is FdRA able to suggest (better) treatment schedules?
• Can FdRA be extended to allow combinatory treatments?
• How to incorporate FdRA into clinical practice?
12
Outlook
Open questions
• Which systems give rise to which response behaviour?
• Can FdRA identify model structures from experiments?
• Is FdRA able to suggest (better) treatment schedules?
• Can FdRA be extended to allow combinatory treatments?
• How to incorporate FdRA into clinical practice?
12
Outlook
Open questions
• Which systems give rise to which response behaviour?
• Can FdRA identify model structures from experiments?
• Is FdRA able to suggest (better) treatment schedules?
• Can FdRA be extended to allow combinatory treatments?
• How to incorporate FdRA into clinical practice?
12
Outlook
Open questions
• Which systems give rise to which response behaviour?
• Can FdRA identify model structures from experiments?
• Is FdRA able to suggest (better) treatment schedules?
• Can FdRA be extended to allow combinatory treatments?
• How to incorporate FdRA into clinical practice?
12
Acknowledgements
• Piet Hein van der Graaf (@certara, @lacdr.leidenuniv)
• James Yates (@astrazeneca)
• Teun Post (@lapp, @lacdr.leidenuniv)
• Vivi Rottschäfer (@math.leidenuniv)
13
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