emea london 2008 - 1 pharmacokinetic- pharmacodynamic integration in veterinary drug development: an...
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EMEA London 2008 - 1
Pharmacokinetic-pharmacodynamic integration in
veterinary drug development: an overview
Pharmacokinetic-pharmacodynamic integration in
veterinary drug development: an overview
P.L. Toutain National Veterinary School ;Toulouse France
EMEA : Focus group meeting on PK/PD
London 24 September 2008
NATIONALVETERINARYS C H O O L
T O U L O U S E
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What is PK/PD?
• PK-PD modeling is a scientific tool to quantify, in vivo, the key PD parameters of a drug, which allow to predict the time course of drug effects under physiological and pathological conditions (intensity and duration)
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What is the main goal of a PK/PD trial
It is an alternative to dose-titration studies to discover an optimal dosage regimen
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An overview on the concept of PK/PD
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Dose titration
Dose ResponseBlack box
PK/PD
Dose
PK PD
Plasmaconcentration
surrogateResponse
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Why is plasma concentration profile a better explicative (independent)
variable than dose for determining a dosage regimen ?
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Dose vs. plasma concentration profile as independent variable
Dose
Mass(no biological information)
Dose F%Clearance
Time
Concentration profile(biological information)
X
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PK/PD applications
1. in vitro to in vivo extrapolation
2. Measure in vivo key PD parameters (efficacy, potency, selectivity, affinity…)
3. predict dosage regimen
4. sources (PK or PD) variability in drug response (antibiotics)
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Application of PK/PD modelling in veterinary medicine
• Antibiotics
• NSAIDs
• ACEI
• Hormones
• others
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An example of application of PK/PD to determine a dosage
regimen for a NSAID in cat
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As for a conventional dose titration, PK/PD investigations generally require a relevant
experimental model (here a kaolin inflammation model)
Possibility to perform PK/PD in patient
EMEA London 2008 - 12Measure of vertical forces exerted on force plate
• To measure the vertical forces, a corridor of walk is used with a force plate placed in its center.
• The cat walks on the force plate on leach.
Video
As for a conventional dose titration, PK/PD investigations require to measure some
relevant endpoints
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• The measure of vertical force and video control are recorded
Vertical forces (Kg)
Video
Measure of vertical forces exerted on force plate
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withdrawal time: timer stopped when cat withdraws its paw
Surrogate endpoint for pain
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Measure of pain with analgesiometer
• Cat is placed in a Plexiglas box.
• A light ray is directed to its paw to create a thermal stimulus.
• The time for the cat to withdraw its paw of the ray is measured.
withdrawal time of the paws (second)
Video
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dRdt
= Kin (1- ) - Kout R Imax + Cn
IC50n + Cn
PK/PD results: analgesic effect
-200
-150
-100
-50
0
50
100
150
0 4 8 12 16 20 24 28 32 36
Time after meloxicam administration (h)
Pai
n sc
ore
(%)
0
200
400
600
800
1000
1200
1400
1600
Mel
oxic
am c
once
ntra
tion
(ng/
mL)
Observed response
Fitted response
Observed concentration
Fitted concentration-200
-150
-100
-50
0
50
100
150
0 4 8 12 16 20 24 28 32 36
Time after meloxicam administration (h)
Pai
n sc
ore
(%)
0
200
400
600
800
1000
1200
1400
1600
Mel
oxic
am c
once
ntra
tion
(ng/
mL)
Observed response
Fitted response
Observed concentration
Fitted concentration-200
-150
-100
-50
0
50
100
150
0 4 8 12 16 20 24 28 32 36
Time after meloxicam administration (h)
Pai
n sc
ore
(%)
0
200
400
600
800
1000
1200
1400
1600
Mel
oxic
am c
once
ntra
tion
(ng/
mL)
Observed response
Fitted response
Observed concentration
Fitted concentration
•Emax/Imax•EC50•Slope
The 3 structural PD parameters: Dose titration (DT) vs. PK/PD
Emax ED50/EC50
SlopeSensitivity
shallow
steep
ED502
Emax 1
Efficacy Potency• Range of useful
concentrations
• Selectivity
Emax 2
1
2
12
ED501
DT & PK/PD: Same Emax
ED50 vs EC50 Only PK/PD
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Simulated dose-response: Drug xxx: analgesic effect
-250
-200
-150
-100
-50
0
50
100
0 4 8 12 16 20 24
Time (h)
Pai
n s
core
(%
)
0.1 mg/kg
0.2 mg/kg
0.3 mg/kg
0.4 mg/kg
0.5 mg/kg
1 mg/kg
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Simulations drug xxxx: once vs. twice a day
Mean effect 32 % Mean effect 52 %
Simulated time course of pain
0
10
20
30
40
50
60
70
80
90
100
0 4 8 12 16 20 24
Time (h)
Pai
n (%
)
5 mg/kg
2 x 2.5 mg/kg
5 mg/kg split in 12
Mean effect 96 %
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Why to prefer a PK/PD approach to a classical
dose-titration?
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ED50 - is a hybrid variable (PK and PD)
- is not a genuine PD drug parameter
PD
1. ED50 vs EC50
A variable vs. a parameter
ilityBioavailab
ECclearancePlasmaED 50
50
_
PK
EC50 is a PD parameter allowing extrapolation•Between formulations•Between physiological status (renal failure)•Between species
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Why to prefer a PK/PD approach to a classical dose-titration?
2.The separation of PK and PD variability
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PK/PD variability
• Consequence for dosage adjustment
PK PD
Dose
Plasma concentration
EffectBODY Receptor
Kidney functionLiver function...
Clinical covariables• disease severity or duration
• pathogens susceptibility (MIC)
PK/PD population approach
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PK Variability
n = 215
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
-5 0 5 10 15 20 25 30
Time (h)
Con
cent
ratio
ns m
g/m
L
Doxycycline
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MIC distributionPasteurella multocida (n=205)
0
MIC (g/mL)
5
10
15
20
25
30
35
40
0.06250.125 0.25 0.5 1 2 4
Pat
ho
gen
s %
SUSCEPTIBLE
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Dosage regimen: application of PK/PD concepts
The 2 sources of variability : PK and PDPK: exposure PD: MIC
Distribution of PK/PD surrogates (AUC/MIC)
Monte-Carlo approach
AUC [0, 24 h] Distribution
0
2
4
6
8
10
12
14
16
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20AUC (µg.h.mL-1)
Fréq
uenc
es (%
)
0
MIC (g/mL)
5
10
15
20
25
30
35
40
0.06250.125 0.25 0.5 1 2 4P
ath
og
ens
%
SUSCEPTIBLE
0
MIC (g/mL)
5
10
15
20
25
30
35
40
0.06250.125 0.25 0.5 1 2 4P
ath
og
ens
%
SUSCEPTIBLE
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Metaphylaxis: dose to achieve a POC of 90% i.e. an AUC/MIC of 80 h
(Drug xxxx: empirical antibiotherapy)
Dose distribution
The main limits of the PK/PD modeling
The main limits of the PK/PD modeling:
Clinical validity of surrogates
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Biomarker and surrogate for NSAID
EC50 in vivo effect
Plasma concentration
Inhibition of COX
Inhibition of PGE2
production
Suppression of lameness
Requires 95% PGE2 inhibition
EC50 responseEC50 response >> EC50 effect
EC50actionWhole blood assay
Clinical endpoint vs. surrogate/biomarkers
• True clinical endpoints are patient feeling, wellbeing, survival rate etc.– because therapeutic endpoints may
be unavailable, impossible to evaluate, time taking…
biomarkers & surrogates
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Measuring responsee.g.: ACE inhibitors
biomarker
surrogate
Clinical outcome
Binding affinity
ACE inhibition
Renin/angiotensin aldosterone modulation
Blood pressure
Survival timeWell-being
Continuity Objectivity Sensitivity
reproducibility
Validity +++
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PK/PD modeling Modelling issues:
Need professional skill
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PK / PD modelling CONCLUSION
• A powerful tool for many applications
• Requires clear understanding of theoretical background and computer software
• Veterinary pharmacologists should be encouraged to consider PD, and not only PK.
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PK / PD modelling CONCLUSION
• The pharmaceutical industry must not hesitate to introduce state-of-art science and technology into its R&D, due to concerns about regulatory impacts