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ECOLE NATIONALE VETERINAIRE T O U L O U S E. 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.

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Pl toutain umr 181 physiopathologie et toxicologie exp rimentales inra envt

ECOLE

NATIONALE

VETERINAIRE

T O U L O U S E

Festschrift in honour of Professor Peter LeesPK/PD modelling of NSAIDs in domestic animalsThe Royal Veterinary College Camden Campus: 22nd July 2010

PL Toutain

UMR 181 Physiopathologie et Toxicologie Expérimentales

INRA, ENVT


1795 rev edward stone described the antipyretic properties of the willow
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).



Brander pugh 1977 no chapter on nsaids
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
Veterinary Pharmacology & Therapeutics No chapter on NSAIDs

1982



Historically aspirin was not appropriately used in veterinary medicine
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
The fallacy of allometric scaling for Aspirin veterinary medicine

  • Extrapolation from man to animal using the Surface Law and Metabolic Body Weight was popular.


Simple allometry the log log transformation
Simple allometry: veterinary medicine the log-log transformation

Plasma Half-life

Y=aBWb

Body weight


The fallacy of allometric scaling for aspirin1
The fallacy of allometric scaling for Aspirin veterinary medicine

  • 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.


A double log plot of salycilate half life in different species

Half-life (h) veterinary medicine

Body Weight (KG)

A double log plot of salycilate half-life in different species


The lloyd e davis paper 1972
The Lloyd E. Davis’ paper (1972) veterinary medicine

  • 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 19721
The Lloyd E. Davis’ paper (1972) veterinary medicine

  • 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
PK : Concepts and practice veterinary medicine

1977


The main limiting factors to conduct pk studies in the late 1970 s
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 s1
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
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
Computer: The main limiting factors to conduct PK & PK/PD studies

From Lisboa (2003) to Toulouse (2009)



Why to investigate nsaids
Why to investigate NSAIDS studies

  • 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)





Condition of the GI tract and oral domestic species

PBZ absorption

The presence of food in the stomach can have a marked

and often unpredictable effect on drug absorption

16

Concentration (µg/ml)

12

8

8

4

4

0

8

0

4

12

24h

12

24h

Hay at the time of

administration and 5 h after

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
The today most cited Peter’s paper domestic speciesand the second most cited RVC paper


PD domestic species

PK



Peter s first pk pd paper
Peter’s first PK/PD paper domestic species


What is pk pd modeling
What is PK/PD modeling? domestic species

  • PK-PD modeling is a scientific tool to quantify, in vivo, thekey 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 modeling1
What is PK/PD modeling? domestic species

  • 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 titration domestic species

Dose

Response

Black box

PK/PD

Response

surrogate

PK

PD

Dose

Plasma

concentration


The determination of an ed 50 or any ed

PD domestic species

PK

The determination of an ED50 or any ED%

ED50 =

ED50 - is a hybrid parameter (PK and PD)

- is not a genuine PD drug parameter

Clearancextarget EC50

Bioavailability



Measuring variables in pk pd trials

Full concentration time curve domestic species

AUC

Cmax , Cmin

Biomarkers

Surrogate

Clinical outcomes

Measuring variables in PK/PD trials

Measuring exposure

Measuring response


Biomarker definition
Biomarker definition domestic species

  • 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

EC domestic species50 in vivo effect

EC50action

whole blood assay

Inhibition of PGE2

production

Suppression of lameness

Inhibition of COX

NSAID plasma concentration

Requires 95% PGE2 inhibition

EC50 response

Which dependent variable for PK/PD modeling ?

EC50 response >> EC50 effect


Biomarkers and surrogates in drug development
Biomarkers and surrogates in drug development domestic species

NSAID

Drug development

Binding affinity

Screening

Biomarkers

COX inhibition

Learning

Demonstrate the likely chance of efficacy/safety

PGs production

Internal decision making

Local temperature

Pain modulation

Surrogate

Confirming

Demonstrate therapeutic response

Lameness

Registration dossier

Field clinicaloutcome

Wellbeing/Demeanor


Ex vivo biomarker investigation the tissue cage model
Ex Vivo domestic species biomarker investigation:The tissue cage model



The tissue cage model
The tissue cage model domestic species

  • 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 model1
The tissue cage model an IV flunixin administration (1.1mg/kg)

  • 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: an IV flunixin administration (1.1mg/kg)

possible in vivo PK/PD modeling using tissue cage as a surrogate of biophase


Pk pd in vitro vs in vivo
PK/PD: an IV flunixin administration (1.1mg/kg) in vitro vs. in vivo

In vivo

Response

Body

Plasma

concentration

Extrapolation

in vitro  in vivo

Mechanism-based PK/PD

In vitro

Medium concentration

Response

Test system


Robenacoxib selectivity
Robenacoxib selectivity an IV flunixin administration (1.1mg/kg)


Pk pd applications
PK/PD applications an IV flunixin administration (1.1mg/kg)

  • in vitro to in vivo extrapolation

  • identify key PD parameters (efficacy, potency, selectivity, affinity…)

  • predict dosage regimen

  • sources (PK or PD) variability in drug response (antibiotics)


Application of pk pd to determine a dosage regimen for nsaids

Application of PK/PD to determine a dosage regimen for NSAIDs

Ketoprofen

Tolfenamic acid

PBZ

Flunixin Meloxicam Ketoprofen

Meloxicam

Nimesulide

Tolfenamic acid COXIB

Meloxicam

Coxib


Modeling options regarding presence or not of a delay between pk and pd time development
Modeling options regarding presence or not of a delay between PK and PD time development

Emax x Cobserved

EC50 + Cobservedl

No PK modeling

E =

NO

Emax x C(t)model

EC50 + C(t)model

PK modeling

E =

PK and PD delay

Effect compartment model

PK origin

YES

Indirect response model

PD origin


Concentration vs time c t and effect vs time e t profiles
Concentration vs time (C(t)) and between PK and PD time development effect vs time (E(t)) profiles

3

5

  • Effect lags behind concentration

    • for a given concentration (1) there are 2 possible effects

    • this makes data analysis difficult

4

2

4

Effect

6

5

4

5

(Anticlockwise)

hysteresis loop

6

3

Concentration or effect

3

1

E(t)

6

1

2

C(t)

2

1

C(t)

Time

t1

t2

delay


Decision tree to select a PK/PD model according to the origin of the delay between the plasma concentration and observed effect.


The effect compartment model
The “effect compartment model” origin of the delay between the plasma concentration and observed effect.

Dose

Cp(t)

Effect(t)

Ce(t)

Ke0

Ke0

Effect

Concentration

Effect

effect

Time

Ce

Time

K10

3:PD model

Parametric (Emax, Hill)

Non parametric (spline)

1:PK model

Parametric (Exponential)

Non parametric (Spline)

2:Link model

Ke0


The effect compartment model flunixin ketoprofen in horses
The “effect compartment model” origin of the delay between the plasma concentration and observed effect.Flunixin & Ketoprofen in horses

K21

Central

1

Peripheral

2

K12

K10

K1e

Effect

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
Freund adjuvant arthritis in horse an IV flunixin administration (1.1mg/kg)

Carpitis


Pk pd flunixine
PK / PD: flunixine an IV flunixin administration (1.1mg/kg)


Pd parameters for different nsaids
PD parameters for different NSAIDs an IV flunixin administration (1.1mg/kg)


PK/PD: Flunixine an IV flunixin administration (1.1mg/kg)

DOSE mg/kg

1

2

16

Stride length (cm)

8

0.5

0

4

16

20

0

8

12

24 h


Pk pd phenylbutazone
PK/PD: Phenylbutazone an IV flunixin administration (1.1mg/kg)

DOSE mg/kg

14

2

4

1.5

12

8

Stride length (cm)

1.25

4

Time(h)

1.0

0

0

4

8

12

16

20

24


A new class of PK/PD models an IV flunixin administration (1.1mg/kg)


Mechanism-based PK/PD modeling in drug discovery an IV flunixin administration (1.1mg/kg)

PK

PD

Response

Dose

Plasma

concentration

Response

Dose

Plasma concentration

Drug receptor interaction

Transduction

System specificity

Drug specificity

affinity

intrinsic efficacy

Pharmacogenomics


1:Dose titration an IV flunixin administration (1.1mg/kg)

Black box

Dose

Response

2:Empirical PK/PD model

Plasma concentration

as driving force

into PD model

PK

Internal dose

PD

Dose

Disease progression

 production

Complexity of model

3:Semimechanistic model

Dose

Biomarker response

Clinical response

-

-

+

+

Biosignal

flux

Biophase

distribution

Plasma

Transduction

Biosensor

process

 loss

Feedback loop


The building of pk pd models
The building of PK/PD models an IV flunixin administration (1.1mg/kg)

  • 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.



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


Measure of vertical forces exerted on force plate

As for a conventional dose titration, PK/PD investigations require to measure some relevant endpoints

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


Measure of vertical forces require to measure some relevant endpointsexerted on force plate

  • The measure of vertical force and video control are recorded

  • Vertical forces (Kg)

Video


Surrogate endpoints locomotion tests
Surrogate endpoints: locomotion tests require to measure some relevant endpoints

  • descending, climbing and creeping time


Surrogate endpoint for pain
Surrogate endpoint for pain require to measure some relevant endpoints

  • withdrawal time: timer stopped when cat withdraws its paw


Measure of pain with analgesiometer
Measure of pain with analgesiometer require to measure some relevant endpoints

  • 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


Pk pd results analgesic effect

I require to measure some relevant endpointsmax+Cn

IC50n + Cn

dR

dt

= Kin (1- ) - Kout R

PK/PD results: analgesic effect

  • Emax/Imax

  • IC50

  • Slope=n


Simulated dose response robenacoxib analgesic effect
Simulated dose-response: Robenacoxib: analgesic effect require to measure some relevant endpoints


Simulations Robenacoxib: once vs. twice a day require to measure some relevant endpoints

Mean effect  96 %

Mean effect  32 %

Mean effect  52 %


Others reasons to prefer a pk pd approach to a classical dose titration
Others reasons to prefer a PK/PD approach to a classical dose-titration?

The separation of PK and PD variability


Pk pd variability
PK/PD variability dose-titration?

  • Consequence for dosage adjustment

PK

PD

Effect

BODY

Receptor

Dose

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 17 20 49 62

Tolfenamic Ac. 28 9.5 47 48

Prednisolone 12 15 49

T. Haake, 1997


The future of the pk pd modeling

The future of the PK/PD modeling variability of Nimesulide, Tolfenamic Ac. and Prednisolone


Preclinical drug development variability of Nimesulide, Tolfenamic Ac. and Prednisolone

Clinical drug development

Learning

Drug discovery

Approval

Confirming

Predicting

  • Preclinical PK/PD

  • Integrated information supporting go/no go decision

Clinical PK/PD

Population PK/PD

  • To acquire basic knowledge on drug

  • Extrapolation from in vitro to in vivo

  • 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


Conclusion
CONCLUSION variability of Nimesulide, Tolfenamic Ac. and Prednisolone

  • The aim of veterinary pharmacology is to provide a rational basis for the use of drugs in a clinical setting

Now, Yes


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