PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT

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

ECOLENATIONALEVETERINAIRET O U L O U S E

















































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 = 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

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.

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

Body Weight (KG)

Hal

f-lif

e (h

)

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)

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

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

Late 70’: Analog computer

1976

1984

1994

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)

1982

2009

Peter’s work from 1981 to 2010

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 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

The today most cited Peter’s paperand the second most cited RVC paper

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 ResponseBlack box

PK/PD

Dose

PK PD

Plasmaconcentration

surrogate

Response

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%

What kind of data for PK/PD modeling

Measuring responseMeasuring exposure

Measuring variables in PK/PD trials

• Full concentration time curve

• AUC • Cmax , Cmin

• 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

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

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

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

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

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

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

Meloxicam Nimesulide Tolfenamic acid COXIB

MeloxicamCoxib

KetoprofenTolfenamic acid

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 =

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

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

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

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

Flunixin plasma, exudate & transudate concentrations after an IV flunixin administration (1.1mg/kg)

Exudate

Transudate

Freund adjuvant arthritis in horse

Carpitis

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

)

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

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

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

A new class of PK/PD models

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

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

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

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

• The measure of vertical force and video control are recorded

Vertical forces (Kg)

Video

Measure of vertical forces exerted on force plate

descending, climbing and creeping time

Surrogate endpoints: locomotion tests

withdrawal time: timer stopped when cat withdraws its paw

Surrogate endpoint for pain

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

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


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


Fitted concentration-200

-150

-100

-50

0

50

100

150

0 4 8 12 16 20 24 28 32 36


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


Fitted concentration

•Emax/Imax•IC50•Slope=n

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

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 %

Others reasons to prefer a PK/PD approach to a classical dose-

titration?

The separation of PK and PD variability

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

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

The future of the PK/PD modeling

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

CONCLUSION

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

PL Toutain UMR 181 Physiopathologie et Toxicologie Expérimentales INRA, ENVT

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