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All About Salbutamol

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What will the verdict in Froome's salbutamol case?

He will be cleared
43
34%
3 month ban
4
3%
6 month ban
15
12%
9 month ban
24
19%
1 year ban
16
13%
2 year ban
21
17%
4 year ban
3
2%
 
Total votes : 126

13 Aug 2018 12:41

Easiest way is obviously corticosteroids out of competition. Unlike Salbutomol, Corticosteroids have no threshold out of competition and legal to use.
samhocking
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Re: All About Salbutamol

20 Sep 2018 14:46

I wasn’t going to revisit this topic, but when the biggest debate in the Clinic is over Froome’s nationality, it seems like a good time to summarize what I’ve learned about his salbutamol case since he was exonerated.

After I wrote a summary/critique of the Froome case, several months ago, Daren Austin, the GLAXO researcher who convinced WADA/UCI that Froome’s urinary salbutamol level could have occurred without taking more than the maximum allowed amount, got in touch with me, and discussed some general aspects of his work. He asked that I not share his personal communications, and he would not discuss the specifics of Froome’s case, including his salbutamol levels during other stages of the 2017 Vuelta, which I really wanted to know. However, he did make a couple of very general points about salbutamol, which I believe I can share here without violating the spirit of my agreement.

First, he noted that most scientists assumed, incorrectly, that drug concentrations in the urine follow a Gaussian or normal distribution. That is, if you give a group of subjects a fixed dose of salbutamol—or if one subject takes the same dose at different times—the urinary levels at some time after the dose will be distributed as a typical Bell curve. From such a distribution, one can determine a mean and standard deviation, and from these values, one can estimate the probability of any particular urinary level occurring by chance.

For reasons I won’t get into here, usually the distribution is not normal, but log normal. That is, it’s the logarithms of the values that are normally distributed. This is critical to Froome’s case, because in a lognormal distribution, the actual values—as opposed to their logarithms—are skewed to the right. This means that the probability of very high values is considerably greater than one would estimate based on a normal distribution.

The second key point is that there are different kinds of inhalers; in particular, there’s a distinction between the MDI, measured dose inhaler, and the Diskus, in which dry powder is inhaled. A study that was published about a year ago showed that the amount of salbutamol getting into the circulation was 50-100% greater when the MDI was used than when the Diskus was used, despite the fact that the nominal dose inhaled was the same. This is also critical to Froome’s case, because while he used the MDI, some of the studies on which WADA based its criterion used the Diskus. In other words, while Froome may have inhaled no more than the maximum allowed dose of 800 ug, as determined by the MDI, that dose could have been equivalent to much more than the 800 ug dose used by WADA in its Diskus studies.

Austin’s argument was that when these two factors—and several others that I will not get into here—are taken into account, Froome’s salbutamol level had a reasonable probability of occurring despite his not taking more than the maximum allowed dose. Since he didn’t specify what this probability was, and I’m not privy to Froome’s other values, I can’t judge how valid this conclusion is. I did go back and re-evaluate all the published WADA studies assuming a lognormal distribution. I was able to show that their values generally did follow this distribution, in agreement with Austin, but I also established that for most of these studies, the actual mean and SD values, based on a lognormal distribution, still indicated that the probability of Froome’s value was quite low. In 7/8 studies, the probability was < 3%, and the weighted mean of all the studies was about 1.5%.

This probability would be a problem for a test applied to a large number of subjects, as the risk of a false positive would be relatively high, and no doubt this is why WADA has suggested it will lower the maximum amount allowed to be inhaled. Probably the only reason there haven’t been more salbutamol positives in the past is because athletes generally have not taken the full allowed dose. However, as applied only to Froome, this probability indicates that his value—based simply on the lognormal argument, nothing else-- would be quite unlikely to result from an allowed dose. I'll also add that i personally never emphasized the standard deviation argument, anyway, but just noted that out of nearly 200 published samples, none exceeded Froome's value, assuming the correction for urine specific gravity was allowed. This point holds regardless of the nature of the distribution.

As for the inhaler effect, while it’s true that some WADA studies used the Diskus, other studies used the MDI, so their results should be relevant to Froome’s level. In fact, comparison of the results of studies using the two types of inhalers generally does not support the conclusion that the amount of salbutamol getting into the system with the MDI is much greater than with the Diskus. That is, there are studies using the MDI at a given dose which result in urinary levels very similar to those observed when the Diskus was used to inhale the same dose. These studies directly contradict the result of the study that Austin pointed out to me. I don’t know how to resolve this discrepancy, except to note that the latter study only measured amounts of salbutamol in the blood, not in the urine. This shouldn’t matter, but FWIW, there’s no study I’m aware of that compares urinary levels of salbutamol following inhalation with MDI vs. Diskus.

Though Austin didn’t say so, I suspect that one reason WDA/UCI did not publish the report is because it was embarrassing to them. They should have known about the lognormal distribution—I should have known this, too, and that is mea culpa,though again, it doesn't really affect the argument I was making—and they should have known about the difference between the inhalers, though that study was only published shortly before the 2017 Vuelta. They have not come out of this looking good.

Another important factor, noted by UCI when it announced its decision, was the effect of dehydration. Several studies suggest that dehydration can increase urinary levels, not simply because the urine was more concentrated, but even taking into account correction for this concentration. However, a crucial question becomes, how dehydrated was Froome on the day of his positive test? While we don’t know—and I don’t think he himself or his legal/scientific team knows--we do know what his urinary specific gravity (USG) was, and I found a couple of studies that relate USG to body mass. Based on these studies, it appears that Froome had a maximal body fluid loss of 3%. This is in agreement with other studies, discussed earlier in this thread, that indicate that greater loss of body fluid is associated with performance deficits. In fact, most evidence indicates that performance deficits occur at losses of > 1.5- 2.0%, so I would think it unlikely that Froome’s loss exceeded this. When Petacchi tested positive for salbutamol, he had an even greater USG, suggesting an even greater fluid loss. This is quite difficult for me to understand, given he not only won the stage, but on a flat sprint, where the power loss would not at least be partially compensated for by a lower body weight, as in the case of the climbing finish that Froome faced. In any case, it seems that dehydration would have a limited effect on Froome’s levels. One of the studies being touted as relevant to Froome’s levels used a body fluid loss of 5%, and that almost certainly was far more than Froome’s loss.

Austen told me that he was publishing a couple of papers relevant to the salbutamol criterion, though as far as I know, they haven’t appeared yet. Absent the actual report, which apparently will never be released despite promises from various parties, it’s not possible to judge how strong the case was for letting Froome off. But based on what data I’ve seen, I’m pretty sure that the probability of his level occurring without taking more than the allowed amount was still fairly low. When Austin’s role was first announced in the media, a figure of 10% was mentioned, which sounds shockingly high, but which still indicates that he would more likely than not have taken more than the allowed amount. I suspect that what probably carried the day was the argument that he would never intentionally dope with salbutamol during a race when he knew he would be tested. So even a relatively low probability would be higher than the probability of the alternative.
Last edited by Merckx index on 14 Oct 2018 19:34, edited 1 time in total.
Merckx index
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20 Sep 2018 17:14

MI nice work
but
how come it's CF the hits a high log-normal score and nobody else?
User avatar TourOfSardinia
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Re:

20 Sep 2018 19:43

TourOfSardinia wrote:MI nice work
but
how come it's CF the hits a high log-normal score and nobody else?


I think we would know if only WADA had followed its own rules and required a pharmacokinetic study........our hapless hero is a 'lucky doper' :)
gillan1969
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20 Sep 2018 21:51

Thanks for the post MI - did Daren Austin have access to Froome's other samples from the Vuelta?
"Are you going to believe me or what you see with your own eyes?"

“It doesn’t matter what I do. People need to hear what I have to say. There’s no one else who can say what I can say. It doesn’t matter what I live.”
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Re:

20 Sep 2018 22:27

TourOfSardinia wrote:MI nice work
but
how come it's CF the hits a high log-normal score and nobody else?


That’s a good question. We don’t know the actual values in all salbutamol positives, but almost all that have been published were lower than Froome’s. I wish all the values were published, so we could find out exactly where Froome stands relative to prior cases. Clearly a major point made by his defense is that very few athletes have ever inhaled the maximum allowed dose. If they did, regularly, then we would expect to see more values over the limit, and maybe some values higher than Froome's. But as with so many other aspects of the case, there is so much we don’t know.

Robert5091 wrote:Thanks for the post MI - did Daren Austin have access to Froome's other samples from the Vuelta?


He had access to the urinary concentrations of those samples, yes. They were essential to his argument. The actual samples, I doubt, but he didn't need them.
Merckx index
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Re: All About Salbutamol

14 Oct 2018 19:07

Austin suggesting Froome could have ingested 1600ugs instead of the allowable 800
Wow...no wonder Froome overdosed

You might also be interested to know that the MDI (blue puffer) delivers about double the systemic salbutamol level of the dry powder inhaler (DPI) for the same lung effect. So if you are using an MDI at the highest allowed dose, you will be more likely to have higher urine levels. The studies previously looking at dehydration used DPI not MDI. -djaustin
http://www.timetriallingforum.co.uk/index.php?/topic/128395-froome-cleared/&page=5
Last edited by 70kmph on 14 Oct 2018 21:16, edited 3 times in total.
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Re: All About Salbutamol

14 Oct 2018 19:34

70kmph wrote:Austen suggesting Froome could have injested 1600ugs instead of the allowable 800
Wow...no wonder Froome overdosed

You might also be interested to know that the MDI (blue puffer) delivers about double the systemic salbutamol level of the dry powder inhaler (DPI) for the same lung effect. So if you are using an MDI at the highest allowed dose, you will be more likely to have higher urine levels. The studies previously looking at dehydration used DPI not MDI. -djaustin
http://www.timetriallingforum.co.uk/index.php?/topic/128395-froome-cleared/&page=5


Yes, I covered that in my post above. It's true that there has been a study comparing the two types of inhalers, and that when the same nominal doses are taken, the blood concentrations of salbutamol are 60-100% greater following the MDI. Also, a few of the salbutamol anti-doping studies provided serum data which support this. But as I noted above, there have been studies using the MDI that found much lower levels than the usually cited study by Haase using 1600 ug.

I hadn't seen that forum before. Since Austin posted on it, anything he says there can of course be discussed. I noticed he mentioned Petacchi's data, which he discussed a little in his private communications with me. He noted that Petacchi should have gotten off, but that was obvious anyway, because if the USG correction has been applied, his salbutamol level would have been well below the threshold. What's especially interesting about Petacchi's data, though, is that they indicate a much lower variability than is reported in inter-subject studies. This is what one would expect in data from a single subject, but if Froome's variability were similar, then it would make it more difficult for a model like Austin's to predict that he could exceed the threshold or decision limit very often. I would really like to see Froome's data, but of course WADA is too chicken-sh!t to publish them.
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14 Oct 2018 20:59

Dr Daren Austin was a speaker at American Conference on Pharmacometrics regarding his work clearing Froome last week. Might be possible to get his slides perhaps MI?
Image
samhocking
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Re:

15 Oct 2018 08:04

samhocking wrote:Dr Daren Austin was a speaker at American Conference on Pharmacometrics regarding his work clearing Froome last week. Might be possible to get his slides perhaps MI?
Image


or.......how not doing a pharmokinetic study helped Froome retain....... ;)
gillan1969
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15 Oct 2018 09:15

So convenient
Veni, Vidi, Kirby

I came, I saw, I was dead wrong as per usual
User avatar Red Rick
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15 Oct 2018 10:29

http://www.go-acop.org/index.php?option=com_content&view=article&id=122:acop9-program&catid=20:site-content&Itemid=108
"Modeling without Bounds" Special Session by Daren Austin: How Pharmacometrics helped Chris Froome win the 2017 Vuelta e España

30 min chat on Dawg's presumed AAF.
"Are you going to believe me or what you see with your own eyes?"

“It doesn’t matter what I do. People need to hear what I have to say. There’s no one else who can say what I can say. It doesn’t matter what I live.”
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Re: Re:

15 Oct 2018 10:31

gillan1969 wrote:
samhocking wrote:Dr Daren Austin was a speaker at American Conference on Pharmacometrics regarding his work clearing Froome last week. Might be possible to get his slides perhaps MI?
Image

or.......how not doing a pharmokinetic study helped Froome retain....... ;)


WADA RMP clearly shows pharmokinetic study is required once the AAF is confirmed. WADA would not confirm the AAF after the athlete explanation phase and so then the UCI entered into an ad-hoc procedural agreement to continue via tribunal instead, so the AAF remained presumptive only.

Following notification of the presumptive AAF in September 2017, the UCI and Mr. Froome, on 28 December 2017, entered into an ad-hoc procedural agreement (WADA was not involved in any fashion in the process leading to this procedural agreement). The UCI and Mr. Froome agreed that Mr. Froome’s evidentiary requests would be decided by the UCI Anti-Doping Tribunal. The requests were ultimately determined by the tribunal in mid-March 2018 after substantial submissions by Mr. Froome and the UCI.


So basically, UCI & Froome agreed an ad-hoc tribunal agreement outside WADA RMP and this tribunal was being used as the AAF Confirmation Procedure, not the Pharmokinetic Study. This is probably because Salbutomol would have been written in each anti-doping control form by Froome I assume?

3.4.2.2 Glucocorticosteroids and Beta-2 Agonists

For these substances, some Laboratories report a Presumptive Adverse Analytical
Finding
to the Testing Authority and enquire if a Confirmation Procedure is required.
The Testing Authority(or RMA, if a different ADO) then checks if a TUE has been
granted, and/or contacts the Athlete to enquire about the route of administration

Image

samhocking
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Re: Re:

15 Oct 2018 12:37

samhocking wrote:
gillan1969 wrote:
samhocking wrote:Dr Daren Austin was a speaker at American Conference on Pharmacometrics regarding his work clearing Froome last week. Might be possible to get his slides perhaps MI?
Image

or.......how not doing a pharmokinetic study helped Froome retain....... ;)


WADA RMP clearly shows pharmokinetic study is required once the AAF is confirmed. WADA would not confirm the AAF after the athlete explanation phase and so then the UCI entered into an ad-hoc procedural agreement to continue via tribunal instead, so the AAF remained presumptive only.

Following notification of the presumptive AAF in September 2017, the UCI and Mr. Froome, on 28 December 2017, entered into an ad-hoc procedural agreement (WADA was not involved in any fashion in the process leading to this procedural agreement). The UCI and Mr. Froome agreed that Mr. Froome’s evidentiary requests would be decided by the UCI Anti-Doping Tribunal. The requests were ultimately determined by the tribunal in mid-March 2018 after substantial submissions by Mr. Froome and the UCI.


So basically, UCI & Froome agreed an ad-hoc tribunal agreement outside WADA RMP and this tribunal was being used as the AAF Confirmation Procedure, not the Pharmokinetic Study. This is probably because Salbutomol would have been written in each anti-doping control form by Froome I assume?

3.4.2.2 Glucocorticosteroids and Beta-2 Agonists

For these substances, some Laboratories report a Presumptive Adverse Analytical
Finding
to the Testing Authority and enquire if a Confirmation Procedure is required.
The Testing Authority(or RMA, if a different ADO) then checks if a TUE has been
granted, and/or contacts the Athlete to enquire about the route of administration

Image



the bolded

looks like you are trying to rewrite the WADA rules...to be fair they rewrote themselves so fair play ;)

you are of course 100% wrong...the rules state

The presence in urine of salbutamol in excess of 1000 ng/mL
or formoterol in excess of 40 ng/mL is not consistent with
therapeutic use of the substance and will be considered as an
Adverse Analytical Finding (AAF) unless the Athlete proves,
through a controlled pharmacokinetic study, that the
abnormal result was the consequence of a therapeutic dose
(by inhalation) up to the maximum dose indicated above.

the study comes before the confirmation...it should be part of your defence......well, it would be if it gave you a defence ;) ;)
gillan1969
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15 Oct 2018 13:26

Classic rewriting of history is amazing, see first sentence

Image
User avatar 70kmph
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15 Oct 2018 13:56

gillan1969, you are stating the rules that apply to a confirmed AAF.
70kph. Glucocorticosteroids and Beta-2 Agonists report a Presumptive Adverse Analytical That has nothing to do with B confirming A. Exclusively for Glucocorticosteroids and Beta-2 Agonists the rules clearly state the RMA, should verify the route of administration used as part of its Initial Review before prosecuting a case as an AAF. That is the part of the rules Froome's AAF got to. If UCI had begun prosecuting as an AAF, then Froome would have had to have take the pharmo test. This is the same as Ullissi exactly.
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Re:

15 Oct 2018 14:26

samhocking wrote:gillan1969, you are stating the rules that apply to a confirmed AAF.
70kph. Glucocorticosteroids and Beta-2 Agonists report a Presumptive Adverse Analytical That has nothing to do with B confirming A. Exclusively for Glucocorticosteroids and Beta-2 Agonists the rules clearly state the RMA, should verify the route of administration used as part of its Initial Review before prosecuting a case as an AAF. That is the part of the rules Froome's AAF got to. If UCI had begun prosecuting as an AAF, then Froome would have had to have take the pharmo test. This is the same as Ullissi exactly.


that's the rules...there's no ambiguity...they are as quoted...and the reading's an AAF unless you do the test...and he didn't do the test

I know some ambigiuty has been introduced (that's what lawyers are for) but the rules themselves allow for none...if the reading is over a certain amount, the way around that is to undertake the study.......and he....er.....didn't undertake the study

there's only so many way to say that

I presume you'd like our hapless hero to release his own readings?...that way we could all see if his metabolism tended to act in the manner that might present a false postive?
gillan1969
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Re: All About Salbutamol

15 Oct 2018 14:33

Whats the cut off point for any fresh doping revelations coming out of the 2018 season.... The Clinic is in desperate need of something to see us through the off season; surely we cant survive a full winter still poring over the scraps of last years news :sad:
brownbobby
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Re: Re:

15 Oct 2018 14:55

gillan1969 wrote:
samhocking wrote:gillan1969, you are stating the rules that apply to a confirmed AAF.
70kph. Glucocorticosteroids and Beta-2 Agonists report a Presumptive Adverse Analytical That has nothing to do with B confirming A. Exclusively for Glucocorticosteroids and Beta-2 Agonists the rules clearly state the RMA, should verify the route of administration used as part of its Initial Review before prosecuting a case as an AAF. That is the part of the rules Froome's AAF got to. If UCI had begun prosecuting as an AAF, then Froome would have had to have take the pharmo test. This is the same as Ullissi exactly.


that's the rules...there's no ambiguity...they are as quoted...and the reading's an AAF unless you do the test...and he didn't do the test

I know some ambigiuty has been introduced (that's what lawyers are for) but the rules themselves allow for none...if the reading is over a certain amount, the way around that is to undertake the study.......and he....er.....didn't undertake the study

there's only so many way to say that

I presume you'd like our hapless hero to release his own readings?...that way we could all see if his metabolism tended to act in the manner that might present a false postive?



That's not ambiguity, that is how WADA stated Froome's AAF as 'presumed' not me, because that is how the lab reports it and WADA guidelines describe it too until confirmed. The lab doesn't know if it's theraputic via route of allowed administration. Also 20% of other above threshold salubutomol cases from 2013 to 2015 resulted in aquittal too, so hardly unique to Froome, other than Froome's circumstances it seems?

Anywya we went round and round in circles at the time. I'm happy the rules were followed, you are not convinced they were, so not much we can do about that.
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Re: All About Salbutamol

15 Oct 2018 14:58

brownbobby wrote:Whats the cut off point for any fresh doping revelations coming out of the 2018 season.... The Clinic is in desperate need of something to see us through the off season; surely we cant survive a full winter still poring over the scraps of last years news :sad:


It is a bit telling how dull the clinic is once anti-doping is not about Sky anymore. Says a lot about people's real motivations to fight the good fight and rider preferences lol!
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