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How to use irrelevant plasma and urine drug concentration in doping

control in the FEI.

PL ToutainUMR 181 Physiopathologie et Toxicologie Expérimentales; INRA, ENVT; 22nd July 2010

ECOLENATIONALEVETERINAIRET O U L O U S E

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Objectives of the presentation

• To explain the EHLSC risk analysis approach:– To determine Irrelevant Plasma (IPC) & Irrelevant Urine

Concentration (IUC)– To select an International Screening Limit (ISL)– To obtain a Detection Time (DT)– To transform a DT to a Withdrawal Time (WT)

• In order to see how FEI can used these information either directly or after its own risk analysis.

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The European Horse Scientific Liason Committee

The view expressed in this presentation are those of the author and do not commit the official policy of the EHLSC

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An anti-doping program is first characterized by a set of values

• Sound science does not exist as 'ready for use' in the policy development process; – Before to explore how FEI can use

International Screening Limits (ISL) as derived by EHSLC, FEI should formally express its set of values:

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What is a clean sport?

• Only a level playing field?

• Does this include protection of the horse?

–If yes, what is the priority: to protect the horse or to protect a business model?

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Science vs. values

• It should be admitted that science is not able to resolve FEI choices about what should be done in the case of competing interests.

• Science is universal, not ethics

• A risk for FEI is to raise a question that is mainly of ethical nature and attempt to solve it using scientific arguments

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An anti-doping program is first characterized by a set of values

• Prohibition of the presence of any substances which could give a horse an advantage or a disadvantage in a horse during a race (or training)

• BUT:• The goal of the EHSLC policy is not to indirectly impede

bona fide veterinary medications – and EHSLC have established a general policy that distinguishes

the control of any drug exposure for all illicit substances (doping control) and the control of a drug effect for therapeutic substances (medication control).

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Testing exposure and the end of a zero tolerance approach for medication control

Need for limitation on the sensitivity of testing for therapeutic agents

!

(ng/ml)

10

1.0

0.1

20 50 100 Time (days)

5 h

2 days

20 days

Detection time

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The current analytical techniques are very performing and laboratory equipments are not a

limiting factors to the efficiency of most drugs

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Testing exposure and the end of a zero tolerance approach for medication control

• Increasing sensitivity of analytical techniques is :– Desirable for potent illegitimate drugs– Unsuitable for therapeutic substances

• because trace concentrations of therapeutic substances totally irrelevant in terms of effects, may be detected a long time after their administration

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Doping control policy at time of racing

• The EHSLC' question– How to avoid to detect trace level of drugs

without any pharmacological meaning

• The question in operational terms– What should be the order of magnitude of

LOD (LOQ) of analytical techniques for the control of drug effect (not drug exposure )

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The “zero tolerance rule” is not suitable for medication control

• This opens the way to a new approach for legitimate medication based upon PK/PD principles to estimate the order of magnitude of the so-called irrelevant drug concentrations in plasma and urine and to limit the sensitivity of analytical techniques used for medication control.

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The decision making process on no significant effect levels

by EHSLC. A risk analysis integrated

approach

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What is risk analysis?

A systematic way of collecting, evaluating and recording information leading to recommendations for a position or action in response to an identified hazard (here medications or illicit substances)

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The 3 main steps of a Risk analysis

1. Risk assessment

2. Risk management

3. Risk communication

Science

Decision

Communication

Irrelevant Plasma concentrationIrrelevant Urine Concentration

International screening limits

Detection Times

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Why a risk analysis

• The reasons to follow a risk analysis are when harmonization is in order, regulatory decisions need to take into account competitive interests in an unbiased and transparent approach.

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FEI will benefit to apply Risk Analysis techniques in making

better decision

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An example: Phenylbutazone

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The 3 main steps of a Risk analysis

1. Risk assessment

2. Risk management

3. Risk communication

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The PK/PD approach to determine irrelevant plasma or

urine drug concentrations

Steps :

1: effective plasma concentration (EPC)

2: Irrelevant plasma concentration (IPC)

3: Irrelevant urine concentration (IUC)

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ED=

ED - is a hybrid parameter (PK and PD)

- is not a genuine PD drug parameter

Clearance x Effective plasma Concentration

Bioavailability

PD

PK

What is exactly an effective dose (ED) ?

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Computation of an Effective Plasma Concentration (EPC)

Clearance

DoseEffectiveEPC

_

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Step 1 : example of phenylbutazone

• Standard dose: 4.4 mg/kg/24 h• Plasma clearance: 41 mL/kg/h or about 1000 mL/kg/24 h

EPC = 4400 µg.kg-1.24h-1

1000 mL.kg-1.24h-1= 4.4 µg/mL

Note: from PK/PD, 1.5 to 4.3 µg/mL

Progressive list : up to 8µg/mL meaning a dose of about 8 mg/Kg/24h

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Freund adjuvant arthritis in horse

Carpitis

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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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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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Step 2: computation of irrelevant plasma concentrations

• An IPC can be deduced from EPC by applying a safety factor (SF) to EPC:

IPC = EPCSF

How to select SF?!

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Step 2: how to select safety factor

SF

Valuesconsiderations

Scientific considerations

• shape of the dose-effect relationship

• paucity of data• class of the drug• large interindividual variability• effect having different potency

Should reflect the degree of confidence we want the IPC is actually an IPC (Values)EHSLC: no effect (2%)

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Safety factor: default EHSLC value=500

• I proposed a default SF = 500

500 = 50 x 10

Transform an EPC into an IPC for a given horse

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Safety factor : 50

Emax100

2

EC50 = EPCEC50

50With a SF=50, effect is about 2% of the effect of interest

Eff

ect

(%)

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Safety factor: default EHSLC value=500

• I proposed a default SF = 500

500 = 50 x 10

Transform an EPC into an IPC for a given horse

Interindividual horse variability

PK variability PD variability

Level playing field require to take into account variability

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Step 2 : the case of Phenylbutazone

by rounding up: IPC= 10 ng/mL

mLngmLngEPC

IPC /8.8500/4400

500

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Step 3: determination of irrelevant urine concentration (IUC)

IUC = IPC x RSS

steady state urine to plasma concentration ratio

urine

Pseudo-equilibrium state

Plasma

10

1

con

cen

trat

ion

(time)

Plasma

Urine

Rss = 10

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Step 3 irrelevant urine concentration (IUC): the case of PBZ

• RSS = 1

• IUC = IPC x RSS

• IUC = 10 ng/mL x 1 = 10 ng/mL

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The 3 main steps of a Risk analysis

Risk assessment

Risk management

Risk communication

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Risk managementDetermination of the ISL

International Screening Limits:

An instruction (expressed as a concentration) to laboratories from racing authorities to control the detection of drugs commonly used in equine medication at a level that is considered NOT to be threat to welfare of the horse, alter its racing or compromise the integrity of racing

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From the IPC/IUC to the ISL

• ISLs are fixed by risk managers (FEI vs. EHSLC)– Risk management is not a scientific exercise but

should be scientifically sound– Possibility to consider at this step non scientific

considerations as harmonization– IPCs/IUCs are starting values

– selection of one of the values of the possible values of

the agreed ordinal scale

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Why an ordinal scale?

• Selection of an ISL is a non quantitative decision and cannot be assimilated to a statistically founded threshold (as for cortisol, testosterone…)

• Results of controls are qualitative (yes or no) and not quantitative

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From IUC to IPC: An hypothetical example

• It is a Anti-inflammatory drug• IUC=38 ng/mL• Possible values of the ordinal scale for a ISL

– 10, 50, 100, 250, 500 etc• The manager will likely choose either 10 or 50 ng/mL,

the 2 values that bracket the IUC• The final choice will take into account the difficulty or

not to harmonize, if the drug is of major concern or not etc.

• It is mainly at that level that FEI can differentiate its conclusions from those of EHSLC

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The 3 main steps of a Risk analysis

Risk assessment

Risk management

Risk communication

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Risk communication

Detection Times vs.

Withdrawal Times

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The question of Detection Time (DT)

• For medication control ISL is not "ready for use" information for veterinarians who must advise owners or trainers on appropriate withholding times.

• Detection time is the only practical information needed by veterinarians and horse industry that EHLSC can release

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What is a detection time•DT is the time at which the urinary (or plasma) concentrations of a drug, in all horses involved in a particular trial conducted according to the EHSLC guidance rules, are observed to be lower than the ISL when controls are performed using routine screening methods.

ISL

time

DT

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Detection Time

• Detection time is not a parameter but a variable without statistical protection

– dose, route of administration, formulation, number of administrations etc.

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Why some DT are so long?

2/144.11

TSF

LnDT

Safety Factor

Half-life (h)

100

DT (days)

500

DT (days)

12 3.31 4.47

24 6.63 8.94

48 13.26 17.89

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From the Detection Timeto a Withdrawal period

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EHLSC decided to release Detection

times (DT) an not Withdrawal time (WT)

• DT: An information given by Authorities without statistical protection

• WT: A Vet recommendation based on his own risk analysis

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Main factors affecting a WT

Dosage regimen:

• Dose

• Dosage interval

• Route of administration

• Site of administration

• etc

Drug

• formulation

• Source

• vehicle

Horse:

• Breed

• Age

• Sex

• Health status

• Food

• Rest/activity

• Training/out of training

Definition and the selected experimental design to determine the WT:

• Number of horses

• Sampling time

• Urine pH

It is not the responsibility of EHLSC to guarantee a WP

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From a detection time to a withdrawal time

• To help the veterinarian select a WT from a published DT the question of a safety span was explored using Monte Carlo Simulations (MCSs) (Toutain 2010.)

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Conclusions

• To help FEI, I will suggest that FEI should:1. Express formally what are its values and amongst

them, what is the priority:– A level playing field vs. animal welfare

2. Follow the principles of the risk analysis to take its decision (ISL) in order to take into account competitive interests in an unbiased and transparent approach.

– Science and management are two different issues– Science can describe the world, but science cannot prescribe

what the world should be

3. Generate its own Detection Times or better, to initiate (participate) to international survey aiming to document factor of variability's of DT (population pharmacokinetics)