Detection by LC-MS/MS of HIF stabilizer FG-4592 used as a new doping agent: Investigation on a positive case

15 Jan 2016

Detection by LC-MS/MS of HIF stabilizer FG-4592 used as a new doping agent : Investigation on a positive case / C. Buisson, A. Marchand, I. Bailloux, A. Lahaussois, L. Martin, A. Molina

  • Journal of Pharmaceutical and Biomedical Analysis 121 (20 March 2016), p. 181-187
  • PMID: 26808067
  • DOI: 10.1016/j.jpba.2016.01.029


Abstract

Stabilizing the labile factor HIF (hypoxia inducible factor) for therapeutic use has led to the development of various molecules by pharmaceutical companies. These HIF stabilizers show promising erythropoiesis stimulating capacities and are of great interest for patients with chronical kidney disease and anemia. Amongst them FG-4592 from FibroGen is now under phase 3 of clinical studies. While this drug is still under investigation, a parallel market already allows to buy this product, which could be tempting for some athletes willing to increase their performances. To avoid such a use for doping purpose, WADA has listed HIF stabilizers and FG-4592 in particular as prohibited substances since 2011 and some anti-doping laboratories have developed a technique of identification of FG-4592 in urine. Here, we described the first case ever identified by an anti-doping laboratory of an athlete using FG-4592. Detection and confirmation in urinary samples was performed by LC-MS/MS. In addition, potential indirect markers erythropoietin (EPO) and hematological parameters followed in the Athlete Biological Passport (ABP) were analyzed during and after the period of use but showed no profound alterations. Only ABPS (abnormal blood profile score) reached (but did not exceed) the upper limit proposed by the ABP adaptive model just after the period of use of FG-4592. Altogether this case sends a warning for anti-doping laboratories which now must strengthen surveillance on HIF stabilizers and develop sensitive methods of detection for this new class of drugs.

lmplementation of the prolyl hydroxylase inhibitor Roxadustat (FG-4592) and its main metabolites into routine doping controls

31 May 2017

lmplementation of the prolyl hydroxylase inhibitor Roxadustat (FG-4592) and its main metabolites into routine doping controls /  Daniel Eichner, Ryan M. Van Wagoner, Mitch Brenner, James Chou, Scott Leigh, Lee R. Wright, Lee A. Flippin, Michael Martinelli, Oliver Krug, Wilhelm Schänzer, Mario Thevis

  • Drug Testing and Analysis 9 (2017) 11-12 (November-December), p. 1768-1778)
  • Special Issue: 35th Cologne workshop: Advances in sports drug testing
  • PMID: 28378453
  • DOI: 10.1002/dta.2202


Abstract

The utility of hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors as a therapeutic means of treating patients suffering from anaemia has been demonstrated for various clinical settings. However, besides this intended use, HIF stabilizers can be the subject of misuse in amateur and elite sports due to their erythropoietic properties, as recently proven by several cases of adverse analytical findings in doping control testing. Consequently, to allow for adequate and comprehensive test methods, knowledge of the drug candidates' metabolism and analytical options enabling appropriate detection windows in sports drug testing samples (i.e., blood and urine) is essential to doping control laboratories. In the present study, a novel HIF prolyl hydroxylase inhibitor referred to as Roxadustat (FG-4592) and main plasma- and urine-derived metabolites were investigated in the context of routine doping control analytical approaches. Liquid chromatography-mass spectrometry-based test methods were used to study the target analytes' dissociation pathways following electrospray ionization and collision-induced dissociation. Diagnostic precursor-product ion pairs were selected to enable the implementation of the intact drug Roxadustat and selected metabolites into multi-analyte initial testing procedures for plasma and urine specimens. The assays were validated in accordance to guidelines of the World Anti-Doping Agency (WADA) and results demonstrated the suitability (fitness-for-purpose) of the employed analytical methods with detection limits ranging from 0.05 to 1 ng/mL and 1 to 5 ng/mL for urine and plasma, respectively. Subsequently, elimination study plasma and urine samples collected up to 167 h post-administration were analyzed using the validated methods, which suggested the use of different target analytes for blood and urine analyses with FG-4592 and its glucuronide, respectively, for optimal detection windows. Additionally, a light-induced rearrangement product (photoisomer) of Roxadustat resulted in the formation of an additional compound of identical mass.

SAIDS 2022_02 SAIDS vs Martinique Potgieter

3 Oct 2022

In May 2022 the South African Institute for Drugfree Sport (SAIDS) has reported an anti-doping rule violation against the Athlete Martinique Potgieter after her sample tested positive for the prohibited substance Cathine.

After notification a provisional suspension was ordered. The Athlete filed a statement in her defence and she was heard for the Independent Anti-Doping Tribunal.

The Athlete admitted the violation and denied the intentional use of the substance. She explained that she had used Sinutab (Cathine) as treatment for her condition for a week and on the morning of the competition.

She was not aware that this over-the-counter medication contained the substance Cathine. Also she mentioned the use of this product the Doping Control Form. She argued that as recreational Athlete she competed without professional support whereas she had not received any anti-doping education.

The Panel accepts that the violation was not intentional and that the recreational Athlete acted with No Significant Fault or Negligence. Although this is the Athlete's second anti-doping rule violation the Panel considers that there are grounds for a reduced sanction.

Therefore the Independent Anti-Doping Tribunal decides on 3 October 2022 to impose a 12 month period of ineligibility on the Athlete starting on the date of the provisional suspension, i.e. on 24 June 2022.

SAIDS 2015_11 Cole Henning vs SAIDS - Appeal

8 Jul 2016

Related cases:

  • SAIDS 2015_11 SAIDS vs Cole Henning
    February 8, 2016
  • CAS 2016_A_4716 Cole Henning vs SAIDS
    March 9, 2017

On 8 February 2016 the South Africa Independent Doping  Hearing Panel (IDHP) decided to impose a 4 year period of ineligibility on the MMA Athlete Cole Henning after he tested positive for the prohibited substance Methylhexaneamine (dimethylpentylamine).

In first instance the Panel concluded that the Athlete acted intentionally and failed in his responsibility to ensure that no prohibited substance enters his system. Hereafter the Athlete appealed this Decision with the Anti-Doping Appeal Committee of South Africa.

The Athlete requested the Appeal Committee to set aside the Appealed Decision and to impose a reduced sanction. He argued that the IDHP and its Appealed Decision was erroneous and that there are grounds for no Significant Fault or Negligence.

The Athlete admitted the violation and denied the intentional use of the substance. He asserted that the substances Methylhexaneamine or Dimethylpentylamine were not listed as ingredient on the label of the supplement TNT-Mercury Napalm he had used.

SAIDS contended that the Athlete acted intentionally because his conduct was reckless or alternatively was significantly negligent.

The Appeal Committee finds that the presence of a prohibited substance has been established in the Athlete's sample and accordingly that he committed an anti-doping rule violation. Further the Committee holds that not had been demonstrated that the supplement TNT-Mercury Napalm was the source of the positive test, nor how the prohibited substance has entered his system.

The Appeal Committee did not accept the Athlete's assertions and deemed that he acted intentionally. The Committee finds that the Athlete muse have known that there was a significant risk that his conduct might result in an anti-doping rule violation and manifestly disregarded that risk.

Therefore the Appeal Committee decides on 8 July 2016 to dismiss the Athlete's appeal and to uphold the Appealed Decision to impose a sanction of 4 years on the Athlete.

SAIDS 2015_11 SAIDS vs Cole Henning

8 Feb 2016

Related cases:

  • SAIDS 2015_11 Cole Henning vs SAIDS - Appeal
    July 8, 2016
  • CAS 2016_A_4716 Cole Henning vs SAIDS
    March 9, 2017

In December 2015 the South African Institute for Drugfree Sport (SAIDS) has reported an anti-doping rule violationa against the MMA Athlete Cole Henning after his sample tested positive for the prohibited substance Methylhexaneamine (dimethylpentylamine).

After notification the Athlete filed a statement in his defence and he was heard for the Independant Doping Hearing Panel.

The Athlete admitted the violation and denied the intentional use of the substance. He explained that he had was unaware that the supplement TNT-Mercury Napalm he had used contained a prohibited substance.

The Athlete stated that this gave him an energy boost and he stopped using this product the day before the match. The Panel established that 1.3 dimethylamylamine (DMAA) was listed on the label of this product.

Considering the Athlete's conduct the Panel concludes that the Athlete acted intentionally and failed in his responsibility to ensure that no prohibited substance enters his system.

Therefore the Panel decides on 8 February 2016 to impose a 4 year period of ineligibility on the Athlete.

World Athletics 2022 WA vs Fernanda Maita

21 Oct 2022

In September 2022 the Athletics Integrity Unit (AIU) on behalf of World Athletics has reported an anti-doping rule violation against the Venezuelan Athlete Fernanda Maita after her sample tested positive for the prohibited substance Enobosarm (Ostarine).

After notification the Athlete gave a prompt admission, waived her right for a hearing, accepted a provisional suspension and the sanction proposed by the AIU. The Athlete did not demonstrate that the violation was not intentional.

Because the Athlete signed and submitted the Admission of Anti-Doping Rule Violations and Acceptance of Consequences Form she received a 1 year reduction from the AIU.

Therefore the AIU decides on 21 October 2022 to impose a 3 year period of ineligibility on the Athlete, starting on the date of the provisional suspension, i.e. on 21 September 2022.

CCES 2022 CCES vs Christine de Bruin

1 Nov 2022

In September 2022 the Canadian Centre for Ethics in Sport (CCES) has reported an anti-doping rule violation against the bobsleigh Athlete Christine de Bruin after her A and B samples tested positive for the prohibited substance LGD-4033 (Ligandrol).

After notification the Athlete gave a prompt admission, waived her right for a hearing, accepted a provisional suspension and the sanction proposed by CCES. Because the Athlete signed and submitted the Early Admission and Acceptance Form she received a 1 year reduction from CCES.

Therefore CCES decides on 4 November 2022 to impose a 3 year period of ineligibility on the Athlete, starting on the date of the provisional suspension, i.e. on 28 September 2022.

CAS 2020_A_7247 Guillermo Bertola vs FINA

25 Jan 2021

CAS 2020/A/7247 Guillermo Bertola v. Fédération Internationale de Natation (FINA)

Related case:

FINA 2020 FINA vs Guillermo Bertola
June 17, 2020


  • Aquatics (swimming)
  • Doping (blood doping)
  • Right of a CAS panel to issue a consent award and purpose of it
  • Duty of the CAS panel to verify the bona fide of the settlement agreemen


1. In accordance with Article R56 para. 2, second sentence, of the CAS Code, a CAS panel is expressly allowed to issue an award embodying the terms of a settlement if all parties to the dispute agree. The panel’s endorsement of the settlement agreement and incorporation in an award serves the obvious purpose of rendering it easier for the parties to enforce the settlement agreement.

2. As any settlement “may” be embodied in an award, it is up to the CAS panel to verify the bona fide of the settlement agreement, so that the consent award mechanism is not manipulated by the parties as an instrument of fraud, and to acknowledge that the settlement terms are not contrary to public policy principles or mandatory rules.



In December 2019 FINA reported an anti-doping rule violation against the Argentine swimmer Guillermo Bertola after an ITA Expert Panel concluded that the Athlete’s hematological profile “highly likely” showed that he had used a prohibited substance or a prohibited method.

Consequently the FINA Doping Panel decided on 17 June 2020 to impose a 4 year period of ineligibility on the Athlete. The FINA Panel concluded that the Athlete failed to demonstrate that he had acted not intentionally when he accepted a blood transfusion from his mother. He also failed to establish grounds for a reduced sanction. 

Hereafter in July 2020 the Athlete appealed the FINA Decision with the Court of Arbitration for Sport (CAS) and thereupon in September 2020 the Parties in this case reached a Settlement Agreement. They requested the Panel to endorse this Settlement Agreement and to render a Consent Award.

The Parties agreed that the sanction of 4 years stands, yet the commencement of the period of ineligibility is backdated by 15 months based on the Athlete's timely admission. Following assessment the Panel deemed that this is a bona fide settlement of the dispute brought to its attention.

Therefore the Court of Arbitration for Sport decides on 25 January 2021 that:

1.) The Settlement Agreement submitted to the CAS Court Office by the Parties on 30 October 2020 is hereby ratified by the CAS with the consent of the Parties and its relevant terms are incorporated into this arbitral award.

2.) The terms of the Settlement Agreement modify Items 6.2 and 6.3 of the decision of the Anti-Doping Panel of the Fédération Internationale de Natation of 17 June 2020.

3.) Each Party is hereby ordered to perform the obligations and duties as per the Settlement Agreement referred to above.

(…)

6.) All other motions or prayers for relief are dismissed.

CAS 2020_A_7579 WADA vs Swimming Australia & SIA & Shayna Jack | SIA vs Shayna Jack & Swimming Australia

16 Sep 2021
  • CAS 2020/A/7579 World Anti-Doping Agency (WADA) v. Swimming Australia (SA), Sport Integrity Australia (SIA) & Shayna Jack; and
  • CAS 2020/A/7580 SIA v. Shayna Jack & SA


Related case:

CAS A1_2020 Shayna Jack vs Swimming Australia & ASADA
November 16, 2020


  • Aquatics (swimming)
  • Doping (ligandrol)
  • Proof of lack of intent
  • Standard of proof for a panel deciding on a reduction of ineligibility
  • Indiscriminate effect of the rules
  • Lack of intent
  • Type of proof
  • Assessment of the evidence


1. Athletes who have committed an anti-doping rule violation (ADRV) and seek to reduce the period of ineligibility under Article 10.2.1 of the World Anti-Doping Code (WADC) need to prove both that they did not intentionally use a prohibited substance and (on the assumption that the explanation given in Article 10.2.3 is binding) that they did not take the risk of using a substance which might lead to an ADRV.

2. In reaching a decision as to whether an appellant deserves a reduction of ineligibility, it is sufficient that a CAS panel base this conclusion on a simple balance of probability, because this is not a decision involving the imposition of disciplinary measure, but rather a reduction of its consequences.

3. The one-size-fits-all characteristics of the rule on reduction of ineligibility may tempt adjudicating bodies to make allowances for specific circumstances – such as the great difference from sport to sport of the likelihood of being able to compete at an elite international level of competition, and thus the different impact of the same period of ineligibility on athletes whose international competitiveness may be of greatly contrasting duration given the physical demands of their sport. But the time and place for making such allowances is when such rules are drafted (and amended), not in making individual decisions.

4. The establishment of the source of the prohibited substance in an athlete’s sample is not mandated in order to prove an absence of intent. In other words, it is possible to prove – albeit with much difficulty – innocent exposure to prohibited substance in the absence of a credible identification of its source. However, as certitude with respect to the source of contamination decreases, so the athlete’s chances of prevailing depend on a counterbalancing increase of the implausibility of bad motive and negligence. The doping hypothesis must no longer (on a balance of probability) make sense in all the circumstances, and the charge of recklessness must (on a balance of probability) be overcome. This can be proved by any means. Identification of the source is often important (but not in and of itself sufficient), but it is not indispensable.

5. Speculations, declarations of a clear conscience, and character references are not sufficient proof. It is an unacceptable paradox to posit that the effect of the apparent unavailability of objective and probative evidence is to give an athlete the same benefit as if s/he had found and presented it. However, if uncorroborated speculation is said not to avail an accused athlete; it should not in fairness avail the accuser either.

6. Assessing evidence in a manner that (i) begins with the science and then (ii) considers the totality of the evidence (iii) through the prism of common sense, possibly (iv) “bolstered” by the athlete’s credibility, is a process that appears to be legitimate as a way of achieving its intended effect of enforcing the rules without finding comfort in the cynical view that occasional harm done to an innocent athlete is acceptable collateral damage.



On 16 November 2020 the Oceania Registry Court of Arbitration for Sport (CAS) decided to impose a 2 year period of ineligibility on the Australian swimmer Shayna Jack after she tested positive for the prohibited substance LGD-4033 (Ligandrol).

In this first instance case the Sole Arbitrator deemed that the Athlete could not demonstrate how the prohibited substance had entered her system but he was willing to accept that the violation was not intentional.

Hereafter the World Anti-Doping Agency (WADA) and Sport Integrity Australia (SIA) appealed this Decision with the Court of Arbitration for Sport (CAS) Appeals Division. They requested the Panel to set aside the Appealed Decision and to impose a 4 year period of ineligibility on the Athlete.

WADA and SIA challenged the Appealed Decision on the grounds that while the Sole Arbitrator acknowledged that in order to reduce the period of ineligibility from 4 years to 2 years the Athlete had the burden to demonstrate that the ADRV was not intentional.

WADA and SIA contended that the Sole Arbitrator erred in relying excessively on the Athlete’s credibility to conclude that she had met that burden and in too readily accepting an absence of intent.

The Panel finds that the Appealed Decision, for all its admirable qualities of discernment and exposition, is not in accordance with the Policy and with what the Panel perceives as consistent strands of leading decisions which contribute to the uniformity of application which is desirable in the international community of elite sports.

The Panel nevertheless upholds the ultimate holding of that Decision in favour of the Athlete, on what it deems to be the balance of probability. It is a close call made with considerable hesitation, indeed by a majority decision with respect to the decisive issue of recklessness under the fact of this case, but close calls must be made, and it favors her for the reasons set forth below.

Therefore the Court of Arbitration for Sport decides on 16 September 2021 that:

  1. The appeal filed by Sport Integrity Australia on 7 December 2021 against Ms Shayna Jack and Swimming Australia Limited concerning the Award rendered in the procedure CAS A1/2020 on 16 November 2020 is dismissed.
  2. The appeal filed by the World Anti-Doping Agency on 7 December 2021 against Sport Integrity Australia, Swimming Australia and Ms Shayna Jack concerning the Award rendered in the procedure CAS A1/2020 on 16 November 2020 is dismissed.
  3. The Athlete’s Period of Ineligibility of two years, commencing on 12 July 2019, determined in the Award CAS A1/2020 on 16 November 2020, is confirmed for the reasons set out in the present Award.
  4. (…).
  5. (…).
  6. (…).
  7. All other motions or prayers for relief are dismissed.

CAS 2017_A_5357 WADA & FIBA vs ESKAN & Olga Chatzinikolaou

31 May 2018

CAS 2017/A/5357 World Anti-Doping Agency (WADA) & Fédération Internationale de Basketball (FIBA) v. Hellenic National Council for Combating Doping (ESKAN) & Olga Chatzinikolaou


  • Basketball
  • Doping (cocaine metabolites)
  • Standard of proof to rebut the intentional committing of an anti-doping rule violation
  • Balance of probability and source of prohibited substance


1. The standard of proof by which an athlete can rebut the presumption of having intentionally committed an anti-doping rule violation or establish specific facts or circumstances is on the balance of probability.

2. The standard of proof of “balance of probability” has to be understood in the way that in case a CAS panel is offered several alternative explanations for the ingestion of the prohibited substance but it is satisfied that one of them is more likely than not to have occurred, the athlete has met the required standard of proof regarding the means of ingestion of the prohibited substance. It remains irrelevant that there may also be other possibilities of ingestion, as long as they are considered by the panel to be less likely to have occurred. In other words, for the panel to be satisfied that a means of ingestion is demonstrated on a balance of probability simply means, in percentage terms, that it is satisfied that there is a 51% chance of it having occurred. The athlete thus only needs to show that one specific way of ingestion is marginally more likely than not to have occurred.



In April 2017 the Hellenic National Council for Combating Doping (ESKAN) has reported an anti-doping rule violation against the basketball player Olga Chatzinikolaou after her A and B samples tested positive for the prohibited substance Cocaine.

Nevertheless the ESKAN Disciplinary Committee accepted the Athlete's explanation that there had been passive inhalation of Cocaine out-of-competition at an afternoon dinner more than 12 hours prior to the game and the Doping Control. Accordinghly the Disciplinary Committee decided on 17 July 2017 not to impose a sanction on the Athlete.

Hereafter in October 2017 the World Anti-Doping Agency (WADA) and the International Basketball Federation (FIBA) appealed the ESKAN Decision with the Court of Arbitration for Sport (CAS).

Furthermore the Athlete's samples were transferred from the Athens Lab to the Lausanne Lab. Reanalysis of these samples revealed that the found concentration of Cocaine was not consistent with her alleged passive inhalation of Cocaine more than 12 hours prior to the game.

WADA and FIBA requested the Panel to set aside the Appealed Decision and to impose a sanction of 4 years. They contended that the Athlete had the burden to demonstrate with corroboration evidence that the violation was not intentional and to prove how the Cocaine had entered her system.

The Athlete denied the intentional use of the substance and requested for a reduced sanction. She asserted that the violation occurred out-of-competition and unrelated to sport performance.

The Sole Arbitrator determines that it was undisputed that the presence of of prohibited substance had been established in the Athlete's samples and accordingly that she committed an anti-doping rule violation.

Following assessment of the evidence the Sole Arbitrator deems finds that the Athlete failed to establish, on a balance of probabilities, her lack of intent nor the source of the Cocaine and the metabolites found in her system.

Therefore the Court of Arbitration for Sport decides on 31 May 2018 that:

1.) The appeal filed on 3 October 2017 by the World Anti-Doping Agency with the Court of Arbitration for Sport against the decision of the Hellenic National Council for Combatting Doping (ESKAN) dated 17 July 2017 is admissible.

2.) The decision of the Hellenic National Council for Combatting Doping (ESKAN) dated 17 July 2017 is set aside.

3.) Ms Olga Chatzinikolaou committed an anti-doping rule violation according to Article 3.1 of the Greek law n° 4373.

4.) Ms Olga Chatzinikolaou is sanctioned with a four (4) year period of ineligibility, starting on 31 May 2018. The period of provisional suspension served by Ms Olga Chatzinikolaou between 13 April 2017 and 17 July 2017, shall be credited against the four-year period of ineligibility to be served.

(…)

7.) All other motions or requests for relief are dismissed.

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