Transcript What is PK/PD modeling? - Physiologie et Thérapeutique Ecole

ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
Festschrift in honour of Professor Peter Lees
PK/PD modelling of NSAIDs in domestic animals
The Royal Veterinary College Camden Campus: 22nd July 2010
PL Toutain
UMR 181 Physiopathologie et Toxicologie Expérimentales
INRA, ENVT
ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
ECOLE
NATIONALE
VETERINAIRE
TOULOUSE
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).
Modern history of
veterinary NSAIDS:
1971 and beyond
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
Veterinary Pharmacology & Therapeutics
No chapter on NSAIDs
1982
Veterinary Pharmacology &
Therapeutics (Ninth Ed.)
2009
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
The fallacy of allometric scaling for
Aspirin
• Extrapolation from man to animal using
the Surface Law and Metabolic Body
Weight was popular.
Simple allometry:
the log-log transformation
y = 10x 0.6
R2 = 1
plasma clearance
Plasma Half-life
1000
100
10
1
0.01
Y=aBWb
0.1
1
Body
weight
Body weight
10
100
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.
Half-life (h)
A double log plot of salycilate half-life in
different species
Body Weight (KG)
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”
The Lloyd E. Davis’ paper on salicylate
(1972)
Plasma salicylate
37h
T1/2h
8.6h
5.9h
1.0h
0.8h
Time
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”
PK : Concepts and practice
1977
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
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
The main limiting factors to conduct PK
& PK/PD studies in the late 1970’s
1976
1984
1994
Late 70’: Analog computer
Computer: The main limiting factors to
conduct PK & PK/PD studies
From Lisboa (2003) to Toulouse (2009)
Why to investigate
NSAIDs in the early
eighties
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)
Peter’s work from 1981 to 2010
2009
1982
The first Peter’s paper on PK of
NSAIDs (1981)
Lack of allometric relationship for different NSAIDS
in domestic species
Condition of the GI tract and oral
PBZ absorption
The presence of food in the stomach can have a marked
and often unpredictable effect on drug absorption
Concentration (µg/ml)
16
12
8
8
4
4
0
0
4
8
12
24h
Hay at the time of
administration and 5 h after
12
24h
Hay 5 h before and at the
time of oral administration
The today most cited Peter’s paper
and the second most cited RVC paper
PK
PD
PK/PD modelling of NSAIDs
in domestic animals
Peter’s first PK/PD paper
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)
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.
Dose titration
Dose
Response
Black box
PK/PD
PK
Response
PD
Dose
Plasma
concentration
surrogate
The determination of an ED50 or any
ED%
PD
ED50 =
Clearance x target EC50
Bioavailability
PK
ED50 - is a hybrid parameter (PK and PD)
- is not a genuine PD drug parameter
What kind of data for PK/PD
modeling
Measuring variables in PK/PD trials
Measuring exposure
• Full concentration
time curve
• AUC
• Cmax , Cmin
Measuring response
• Biomarkers
• Surrogate
• Clinical outcomes
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
Which dependent variable for PK/PD
modeling ?
EC50 in vivo effect
EC50 action
whole blood
assay
NSAID
plasma
concentration
Inhibition
of COX
Inhibition of
PGE2
production
Suppression
of lameness
Requires 95% PGE2 inhibition
EC50 response
EC50 response >> EC50 effect
Biomarkers and surrogates in drug
development
NSAID
Drug development
Binding affinity
Screening
COX inhibition
PGs production
Local temperature
Pain modulation
Lameness
Wellbeing/Demeanor
Biomarkers
Demonstrate the
likely chance of
efficacy/safety
Surrogate
Demonstrate therapeutic
response
Field clinical outcome
Learning
Internal
decision
making
Confirming
Registration
dossier
Ex Vivo biomarker investigation:
The tissue cage model
Development of equine models
of inflammation (1987)
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
Flunixin plasma, exudate & transudate concentrations after
an IV flunixin administration (1.1mg/kg)
Exudate
Transudate
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)
The tissue cage model:
possible in vivo PK/PD modeling using tissue cage as a surrogate of biophase
PK/PD: in vitro vs. in vivo
In vivo
Plasma
concentration
Body
Response
Extrapolation
in vitro  in vivo
In vitro
Medium
concentratio
n
Test
system
Mechanismbased PK/PD
Response
Robenacoxib selectivity
100
% inhibition
80
Fitted COX 1
Fitted COX 2
Observed COX-1
Observed COX-2
60
40
20
0
-20
0.001
0.01
0.1
1
10
CGS 34975 concentration (µM)
100
1000
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)
Application of PK/PD to
determine a dosage regimen
for NSAIDs
PBZ
Flunixin
Meloxicam
Ketoprofen
Ketoprofen
Tolfenamic acid
Meloxicam
Coxib
Meloxicam
Nimesulide
Tolfenamic acid
COXIB
Modeling options regarding presence or not of a
delay between PK and PD time development
No PK modeling
E=
Emax x Cobserved
EC50 + Cobservedl
NO
PK modeling
PK and PD
delay
E=
Emax x C(t)model
EC50 + C(t)model
PK origin
Effect compartment model
PD origin
Indirect response model
YES
Concentration or effect
Concentration vs time (C(t)) and
effect vs time (E(t)) profiles
3
5
4
2
Effect
5
4
5
(Anticlockwise)
6
3
1
6
2
E(t)
t1
t2
hysteresis
loop
3
1
C(t)
1
4
6
2
Time
delay
• Effect lags behind concentration
 for a given concentration (1) there are 2 possible effects
 this makes data analysis difficult
C(t)
Decision tree to select a PK/PD model according to the
origin of the delay between the plasma concentration and
observed effect.
PK or PD
Delay?
No
Yes
Plasma concentration
Directly incorporated in
PD model
What is the origin
of the delay?
PK origin
PD origin
Effect
compartment
model
Indirect effect
model
As raw data
Semi parametric (spline)
From an exponential model
The “effect compartment model”
Dose
effect
Time
Effect
Ke0
Concentration
Ce(t)
Ce
Ke0
Effect(t)
Effect
Cp(t)
Time
K10
1:PK model
Parametric (Exponential)
Non parametric (Spline)
2:Link model
Ke0
3:PD model
Parametric (Emax, Hill)
Non parametric (spline)
The “effect compartment model”
Flunixin & Ketoprofen in horses
K21
Central
1
K10
Peripheral
2
K12
K1e
Effect
E  E0 
E max N  Ce N
EC50N  Ce N
Ke0
Fig 1: PK/PD model applied to the analysis of biological responses
Flunixin plasma, exudate & transudate concentrations after
an IV flunixin administration (1.1mg/kg)
Exudate
Transudate
Freund adjuvant arthritis in horse
Carpitis
Stride length (cm)
Concentration (µg/ml)
PK / PD: flunixine
Time (h)
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
PK/PD: Flunixine
Stride length (cm)
DOSE mg/kg
1
2
16
8
0.5
0
0
4
8
12
16
20
24 h
PK/PD: Phenylbutazone
DOSE mg/kg
Stride length (cm)
14
1.5 2
12
4
8
1.25
4
Time(h)
1.0
0
0
4
8
12
16
20
24
A new class of PK/PD models
Mechanism-based PK/PD
modeling in drug discovery
PK
PD
Response
Dose
Plasma
concentration
Dose
Response
Plasma
concentration
Drug receptor
interaction
Drug specificity
affinity
intrinsic efficacy
Transduction
System specificity
Pharmacogenomics
1:Dose titration
PK
Internal dose
 production
3:Semimechanistic model
PD
Disease progression
Dose
+
Plasma
Biosignal
flux
Biophase
distribution
+
-
Biosensor
process
Transduction
 loss
Feedback loop
Clinical response
Dose
Plasma concentration
as driving force
into PD model
Biomarker response
Complexity of model
2:Empirical PK/PD model
Response
Black box
Dose
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.
An example of application of
PK/PD to determine a dosage
regimen for a NSAID in cat
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
As for a conventional dose titration, PK/PD
investigations require to measure some
relevant endpoints
• 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
Measure of vertical forces exerted on force plate
Measure of vertical forces
exerted on force plate
• The measure of
vertical force and
video control are
recorded
 Vertical forces (Kg)
Video
Surrogate endpoints: locomotion tests
 descending, climbing and
creeping time
Surrogate endpoint for pain
 withdrawal time: timer stopped when cat withdraws
its paw
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.
Video
 withdrawal time of the
paws (second)
150
1600
100
1400
1200
Pain score (%)
50
1000
0
800
-50
600
Observed response
-100
400
Fitted response
-150
Observed concentration
200
Meloxicam concentration (ng/mL)
PK/PD results: analgesic effect
Fitted concentration
-200
0
0
4
8
12
16
20
24
28
32
36
Time after meloxicam administration (h)
Cn
Imax +
dR
= Kin (1) - Kout R
dt
IC50n + Cn
•Emax/Imax
•IC50
•Slope=n
Simulated dose-response:
Robenacoxib: analgesic effect
100
50
Pain score (%)
0
0.1 mg/kg
0.2 mg/kg
0.3 mg/kg
0.4 mg/kg
0.5 mg/kg
1 mg/kg
-50
-100
-150
-200
-250
0
4
8
12
Time (h)
16
20
24
Simulations Robenacoxib: once vs. twice a day
Simulated time course of pain
100
90
80
Pain (%)
70
60
50
5 mg/kg
2 x 2.5 mg/kg
5 mg/kg split in 12
40
30
20
10
0
0
4
8
12
16
20
24
Time (h)
Mean effect  32 %
Mean effect  52 %
Mean effect  96 %
Others reasons to prefer a PK/PD
approach to a classical dosetitration?
The separation of PK and
PD variability
PK/PD variability
• Consequence for dosage adjustment
PK
Dose
PD
BODY
Receptor
Effect
Plasma
concentration
Kidney function
Liver function
...
Clinical covariables
• disease severity or duration
• pathogens susceptibility (MIC)
PK/PD population approach
Interindividual pharmacokinetic and
pharmacodynamic variability of Nimesulide,
Tolfenamic Ac. and Prednisolone
Coefficient of variation
PK
PD
Clearance
Vss
EC50
EC50
antipyretic antiinflamatory
Nimesulide
Tolfenamic Ac.
Prednisolone
T. Haake, 1997
17
28
12
20
9.5
15
49
47
62
48
49
The future of the
PK/PD modeling
Clinical drug development
Approval
Drug discovery
Preclinical drug development
Learning
Confirming
Preclinical PK/PD
•Integrated information supporting go/no go
decision
1. To acquire basic
knowledge on drug
2. Extrapolation from in vitro
to in vivo
Predicting
Clinical PK/PD
Population PK/PD
• To adjust dosage regimen to
different subgroups of
animals (age, sex, breed,
disease)
Predictive PK/PD
3. To be an alternative to
dose-titration studies to
discover an optimal
dosage regimen
• Simulations
• Trial forecasting
CONCLUSION
• The aim of veterinary
pharmacology is to
provide a rational basis
for the use of drugs in
a clinical setting