How to use irrelevant plasma and urine drug concentration in doping control in the FEI.

How to use irrelevant plasma and urine drug concentration in doping

control in the FEI.

PL Toutain

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

ECOLE NATIONALE VETERINAIRE T O U L O U S E

2

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.

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:

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

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

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

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.

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)

The 3 main steps of a Risk analysis

1. Risk assessment

2. Risk management

3. Risk communication

Science

Decision

Communication

Irrelevant Plasma concentration Irrelevant 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.

FEI will benefit to apply Risk Analysis techniques in making

better decision

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An example:

Phenylbutazone

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)

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

Dose Effective

EPC _



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 :

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Freund adjuvant arthritis in horse

Carpitis

12 14

8 4

0

0 4 8 12 16 20 24

Time(h)

Stride length (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

Stride length (cm) 1

0.5

2 DOSE mg/kg

PK/PD: Flunixine

Step 2: computation of irrelevant plasma concentrations

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

IPC = EPC SF

How to select SF?

!

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Step 2: how to select safety factor

SF

Values

considerations

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%)

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

100 Emax

2

EC₅₀ = EPC EC₅₀

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

Effect (%)

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

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Step 2 : the case of Phenylbutazone

by rounding up: IPC= 10 ng/mL mL mL ng

ng

IPC EPC 8 . 8 /

500 / 4400

500  



Step 3: determination of irrelevant urine concentration (IUC)

IUC = IPC x R_SS

steady state urine to plasma concentration ratio

urine

Pseudo-equilibrium state Plasma 10

1

concentration

(time) Plasma

Urine

Rss = 10

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

• R

= 1

• IUC = IPC x R

• IUC = 10 ng/mL x 1 = 10 ng/mL

The 3 main steps of a Risk analysis

Risk assessment

Risk management

Risk communication

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Risk management

Determination 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

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

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

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

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.

Why some DT are so long?

2 /

44

. 1 1

SF T Ln

DT    

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 Time

to a Withdrawal period

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

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)