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Festschrift in honour of Professor Peter LeesPK/PD modelling of NSAIDs in domestic animals The Royal Veterinary College Camden Campus: 22nd July 2010
PL ToutainUMR 181 Physiopathologie et Toxicologie Expérimentales
INRA, ENVT
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1795: Rev Edward Stone described the antipyretic properties of the willow
1897
•1982 Nobel Prize for Medicine for his research on mechanism of action of NSAID (prostaglandins).
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Modern history of veterinary NSAIDS:1971 and beyond
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Brander & Pugh (1977) No chapter on NSAIDs
Originally these drugs (PBZ…) were synthesized in the days of antiseptic surgery as derivatives of phenol which might be capable of exerting internal antisepsis
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Veterinary Pharmacology & Therapeutics
No chapter on NSAIDs
1982
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Veterinary Pharmacology & Therapeutics (Ninth Ed.)
2009
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Historically, aspirin was not (appropriately) used in veterinary medicine
• Historically too expansive for large animals• The doses recommended for small animals are too high.
– Such recommendations for salicylates were rather constant in veterinary pharmacology handbooks in e.g. Germany, USA, Russia and Spain from 1900 up to the 70’s.
• The fallacy of the allometric rule
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The fallacy of allometric scaling for Aspirin
• Extrapolation from man to animal using the Surface Law and Metabolic Body Weight was popular.
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Simple allometry: the log-log transformation
y = 10x0.6
R2 = 1
1
10
100
1000
0.01 0.1 1 10 100
Body weight
pla
sma
clea
ran
ce
Y=aBWb
Pla
sma
Hal
f-li
fe
Body weight
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The fallacy of allometric scaling for Aspirin
• The principal reason for this lack of universal applicability is that allometry deals only with size; specifically, it does not address metabolic differences among species.
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A double log plot of salycilate half-life in different species
Body Weight (KG)
Hal
f-lif
e (h
)
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The Lloyd E. Davis’ paper (1972)
• Introduction:“We believed that information relevant to the biotransformation and rates of disappearance from blood of several drugs in a series of large domestic animals might prove of value”
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The Lloyd E. Davis’ paper on salicylate (1972)
37h
8.6h
5.9h
1.0h
0.8h
T1/2h
Time
Plasma salicylate 37h
8.6h
5.9h
1.0h
0.8h
T1/2h
Time
Plasma salicylate
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The Lloyd E. Davis’ paper (1972)
• Conclusion:“the present data indicate the futility of extrapolating dose and dosage regimens from one species to another, as has been done in the past, in the treatment of domestic animals”
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PK : Concepts and practice
1977
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The main limiting factors to conduct PK studies in the late 1970’s
• During the 70's, most chemical separations were carried out using paper chromatography and thin-layer chromatography
• Only in the late 1970's, reverse phase liquid chromatography allowed for improved separation between very similar compounds
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The main limiting factors to conduct PK studies in the late 1970’s
• By the 1980's HPLC was commonly used for the separation of chemical compounds. New techniques improved separation, identification, purification and quantification far above the previous techniques.. Improvements in type of columns and thus reproducibility were made as such terms as micro-column, affinity columns, and Fast HPLC began to immerge
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The main limiting factors to conduct PK & PK/PD studies in the late 1970’s
Late 70’: Analog computer
1976
1984
1994
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Computer: The main limiting factors to conduct PK & PK/PD studies
From Lisboa (2003) to Toulouse (2009)
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Why to investigate NSAIDs in the early
eighties
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Why to investigate NSAIDS
• All domestic species suffer pain and controlling pain is a priority issue for veterinary pharmacologist
• Inflammation is a major source of pain– Acute (e.g. infectious) or chronic (e.g. osteoarthritis)
• To determine an adequate dosage regimen– Efficacy– Safety
• Selectivity (COX1 vs. COX2)
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1982
2009
Peter’s work from 1981 to 2010
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The first Peter’s paper on PK of NSAIDs (1981)
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Lack of allometric relationship for different NSAIDS in domestic species
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Condition of the GI tract and oral
PBZ absorptionThe presence of food in the stomach can have a marked and often unpredictable effect on drug absorption
24h0 4 8 12
8
4
0
Hay at the time of administration and 5 h after
Concentration (µg/ml)16
12
8
4
Hay 5 h before and at the time of oral administration
24h12
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The today most cited Peter’s paperand the second most cited RVC paper
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PK PD
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PK/PD modelling of NSAIDs in domestic animals
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Peter’s first PK/PD paper
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What is PK/PD modeling?
• PK-PD modeling is a scientific tool to quantify, in vivo, the key PD parameters (efficacy, potency and sensitivity) of a drug, which allows to predict the time course of drug effects under physiological and pathological conditions (intensity and duration)
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What is PK/PD modeling?
• PK/PD modeling is a versatile tool which is mainly used in veterinary medicine to select rational dosage regimens (dose, dosing interval) for confirmatory clinical testing.
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Dose titration
Dose ResponseBlack box
PK/PD
Dose
PK PD
Plasmaconcentration
surrogate
Response
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ED50 =
ED50 - is a hybrid parameter (PK and PD)
- is not a genuine PD drug parameter
Clearance x target EC50
Bioavailability
PD
PK
The determination of an ED50 or any ED%
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What kind of data for PK/PD modeling
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Measuring responseMeasuring exposure
Measuring variables in PK/PD trials
• Full concentration time curve
• AUC • Cmax , Cmin
• Biomarkers• Surrogate • Clinical outcomes
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Biomarker definition
• A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention
Markers of drug response
Markers of disease or physiological function
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Requires 95% PGE2 inhibition
EC50 response
EC50 response >> EC50 effect
EC50 in vivo effectEC50
actionwhole blood
assay
Which dependent variable for PK/PD modeling ?
NSAID plasma
concentration
Inhibition of COX
Inhibition of PGE2
production
Suppression of lameness
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Biomarkers and surrogates in drug development
Demonstrate the likely chance of efficacy/safety
Demonstrate therapeutic response
Internal decision making
Registration dossier
LearninLearningg
ConfirminConfirmingg
Drug development
ScreeninScreeninggBiomarkers
Surrogate
Field clinical outcome
Local
temperature
Pain modulation
Binding affinity
COX inhibition
PGs production
Lameness
NSAID
Wellbeing/Demeanor
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Ex Vivo biomarker investigation:The tissue cage model
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Development of equine models of inflammation (1987)
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The tissue cage model
• PK investigations– Plasma: shallow compartment– Tissue cage: Deep compartment (size effect)– Influence of inflammation on local
concentration of NSAIDs
• PD investigations
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Flunixin plasma, exudate & transudate concentrations after an IV flunixin administration (1.1mg/kg)
Exudate
Transudate
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The tissue cage model
• PK investigations
• PD investigations– Biological liquids for in vitro assays
(transudat, exudates)– Ex vivo investigations (PK/PD integration)– In vivo investigation ( PK/PD modeling)
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The tissue cage model: possible in vivo PK/PD modeling using tissue cage as a surrogate of biophase
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ResponsePlasmaconcentration
Body
Medium concentratio
n
Test system
Response
In vivo
In vitro
Extrapolation in vitro in vivo
Mechanism-based PK/PD
PK/PD: in vitro vs. in vivo
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Robenacoxib selectivity
-20
0
20
40
60
80
100
0.001 0.01 0.1 1 10 100 1000
CGS 34975 concentration (µM)
% in
hib
itio
nFitted COX 1Fitted COX 2Observed COX-1Observed COX-2
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PK/PD applications
1. in vitro to in vivo extrapolation
2. identify 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 to determine a dosage regimen
for NSAIDs
PBZ
Flunixin Meloxicam Ketoprofen
Meloxicam Nimesulide Tolfenamic acid COXIB
MeloxicamCoxib
KetoprofenTolfenamic acid
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Modeling options regarding presence or not of a delay between PK and PD time development
PK and PD delay
NO
YES
No PK modeling
PK modeling
PK origin
PD origin Indirect response model
Effect compartment model
E =Emax x C(t)model
EC50 + C(t)model
Emax x Cobserved
EC50 + Cobservedl
E =
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Concentration vs time (C(t)) and effect vs time (E(t)) profiles
• Effect lags behind concentration for a given concentration (1) there are 2 possible effects this makes data analysis difficult
Effect
(Anticlockwise)
hysteresis loop
C(t)C(t)
E(t)
t1 t2Time
delay
1
2
3
4
5
6
12
3
4
5
6
12
3
4
5
6
Co
nce
ntr
atio
n o
r ef
fect
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Decision tree to select a PK/PD model according to the origin of the delay between the plasma concentration and
observed effect.
PK or PDDelay?
YesWhat is the origin
of the delay?
NoPlasma concentration
Directly incorporated in PD model
PK origin PD origin
Effectcompartment
model
Indirect effectmodel
As raw dataSemi parametric (spline)
From an exponential model
PK or PDDelay?
YesWhat is the origin
of the delay?
NoPlasma concentration
Directly incorporated in PD model
PK origin PD origin
Effectcompartment
model
Indirect effectmodel
As raw dataSemi parametric (spline)
From an exponential model
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The “effect compartment model” Dose
1:PK modelParametric (Exponential)Non parametric (Spline)
2:Link modelKe0
3:PD modelParametric (Emax, Hill)Non parametric (spline)
Ke0 Ke0
K10
Cp(t) Ce(t)
Time
Concentrationeffect
Ce
Eff
ect
Effect(t)
Time
Eff
ect
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The “effect compartment model”Flunixin & Ketoprofen in horses
Central1
Peripheral2
K21
K12K10
Ke0
K1e
Effect
Fig 1: PK/PD model applied to the analysis of biological responses
NN
NN
CeEC
CeEEE
50
0
max
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Flunixin plasma, exudate & transudate concentrations after an IV flunixin administration (1.1mg/kg)
Exudate
Transudate
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Freund adjuvant arthritis in horse
Carpitis
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PK / PD: flunixine
Time (h)
Co
nce
ntr
atio
n (
µg
/ml)
Str
ide
len
gth
(cm
)
Time (h)
Co
nce
ntr
atio
n (
µg
/ml)
Str
ide
len
gth
(cm
)
Time (h)
Co
nce
ntr
atio
n (
µg
/ml)
Str
ide
len
gth
(cm
)
Co
nce
ntr
atio
n (
µg
/ml)
Str
ide
len
gth
(cm
)
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PD parameters for different NSAIDs
PD parameters Efficacy Potency Sensitivity
Drugs Emax (cm) EC50
(µg/mL)
Slope
PBZ 13.6 3.6 >5
Flunixin 22.8 0.93 >5
Meloxicam 27.4 0.19 >5
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8
0
16
0 4 8 12 16 20 24 h
Str
ide
len
gth
(c
m) 1
0.5
2
DOSE mg/kg
PK/PD: Flunixine
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12
14
8
4
00 4 8 12 16 20 24
Time(h)Str
ide
len
gth
(cm
)
1.25
1.0
1.5 2 4
DOSE mg/kg
PK/PD: Phenylbutazone
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A new class of PK/PD models
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Mechanism-based PK/PD modeling in drug discovery
DoseResponse
PK PD
Plasmaconcentration
Plasma concentration
Drug receptor interaction Transduction
DoseResponse
Drug specificityaffinity
intrinsic efficacy
System specificity
Pharmacogenomics
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Co
mp
lexi
ty o
f mo
del
1:Dose titration
Dose Black box
Res
pons
e
Dose PKInternal dose
Plasma concentration as driving force into PD model
Dose
Biophasedistribution
PD
Plasma Biosignalflux
loss
production
Bio
mar
ker
resp
on
se
Cli
nic
al
resp
on
se
Biosensorprocess
Transduction
2:Empirical PK/PD model
3:Semimechanistic model
+ -
+ -
Feedback loop
Disease progression
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The building of PK/PD models
• PK model– transforming dose into concentration vs. time profile;
• Link model – describing transfer of the drug form plasma into the biophase;
• System model– that describes the physiological system or the pathological
process on which the drug is acting;
• PD model – relating biophase concentration to an effect on the system.
• Statistical model – that describes the error component of the model and that is
typically estimated in population PK/PD investigations.
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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
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Measure 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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descending, climbing and creeping time
Surrogate endpoints: locomotion tests
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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•IC50•Slope=n
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Simulated dose-response: Robenacoxib: 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 Robenacoxib: 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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Others reasons to prefer a PK/PD approach to a classical dose-
titration?
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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Coefficient of variation
PK PD
Clearance Vss EC50 EC50
antipyretic antiinflamatory
Nimesulide 17 20 49 62
Tolfenamic Ac. 28 9.5 47 48
Prednisolone 12 15 49
Interindividual pharmacokinetic and pharmacodynamic variability of Nimesulide,
Tolfenamic Ac. and Prednisolone
T. Haake, 1997
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The future of the PK/PD modeling
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Preclinical drug development Clinical drug development
Learning
Dru
g d
isc
ov
ery
Ap
pro
val
Confirming
1. To acquire basic knowledge on drug
2. Extrapolation from in vitro to in vivo
3. To be an alternative to dose-titration studies to discover an optimal dosage regimen
• To adjust dosage regimen to different subgroups of animals (age, sex, breed, disease)
Predictive PK/PD• Simulations• Trial forecasting
Preclinical PK/PD•Integrated information supporting go/no go
decision
Predicting
Clinical PK/PDPopulation PK/PD
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CONCLUSION
• The aim of veterinary pharmacology is to provide a rational basis for the use of drugs in a clinical setting