1. 1 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. 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.

3. 3 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

4. 4 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:

5. 5 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?

6. 6 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

7. 7 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).

8. 8 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

9. 9 The current analytical techniques are very performing and laboratory equipments are not a limiting factors to the efficiency of most drugs

10. 10 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

11. 11 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 )

12. 12 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.

13. 13 The decision making process on no significant effect levels by EHSLC. A risk analysis integrated approach

14. 14 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)

15. 15 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

16. 16 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.

17. 17 FEI will benefit to apply Risk Analysis techniques in making better decision

18. 18 An example: Phenylbutazone

19. 19 The 3 main steps of a Risk analysis 1.Risk assessment 2.Risk management 3.Risk communication

20. 20 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)

21. 21 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) ?

22. 22 Computation of an Effective Plasma Concentration (EPC)

23. 23 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

24. 24 Freund adjuvant arthritis in horse Carpitis

25. 25 12 14 8 4 0 0 4812162024 Time(h) Stride length (cm) 1.25 1.0 1.5 2 4 DOSE mg/kg PK/PD: Phenylbutazone

26. 26 8 0 16 0 4 812 1620 24 h Stride length (cm) 1 0.5 2 DOSE mg/kg PK/PD: Flunixine

27. 27 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? !

28. 28 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%)

29. 29 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

30. 30 Safety factor : 50 Emax 100 2 EC 50 = EPC EC 50 50 With a SF=50, effect is about 2% of the effect of interest Effect (%)

31. 31 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 variabilityPD variability Level playing field require to take into account variability

32. 32 Step 2 : the case of Phenylbutazone by rounding up: IPC= 10 ng/mL

33. 33 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

34. 34 Step 3 irrelevant urine concentration (IUC): the case of PBZ R SS = 1 IUC = IPC x R SS IUC = 10 ng/mL x 1 = 10 ng/mL

35. 35 The 3 main steps of a Risk analysis Risk assessment Risk management Risk communication

36. 36 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

37. 37 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

38. 38 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

39. 39 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

40. 40 The 3 main steps of a Risk analysis Risk assessment Risk management Risk communication

41. 41 Risk communication Detection Times vs. Withdrawal Times

42. 42 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

43. 43 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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46. 46 Detection Time Detection time is not a parameter but a variable without statistical protection –dose, route of administration, formulation, number of administrations etc.

47. 47 Why some DT are so long? Safety Factor Half-life (h) 100 DT (days) 500 DT (days) 123.314.47 246.638.94 4813.2617.89

48. 48 From the Detection Time to a Withdrawal period

49. 49 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

50. 50 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

51. 51 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.)

52. 52 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)