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Back to the forum  Query: 2017-12-13 15:58 CET (UTC+1h)
 
Helmut
Hero
Homepage
Vienna, Austria,
2017-11-26 12:51

Posting: # 18007
Views: 575
 

 Levothyroxine: A black swan? [BE/BA News]

Dear all,

bioequivalence is not science (i.e., challenging a falsifiable hypothesis through experiments) but rather an ad-hoc concept. Its two main assumptions were plucked out of thin air:
  • A 20% difference in rate and extent of absorption is considered clinically not relevant and
  • similar plasma concentrations in healthy subjects can be extrapolated to the patient population (i.e., similar therapeutic effects / AEs are expected).
Though not science in the strict sense, empiric evidence shows that the concept “works”:
  • The few case reports telling the opposite might also be explained by non-compliance or the nocebo effect.
  • Originators trying to dispute the concept (i.e., performing therapeutic equivalence studies in patients v.s. BE) failed: If TE passed, BE passed as well and vice versa.
  • In short: “There are no dead people lying in the streets.” (© Helmut Schütz)
Did we just discover the first black swan?
Following concern by the French ANSM in 2012 about stability issues Merck KGaA changed one of the excipients of their levothyroxine sodium formulation Levothyrox, namely lactose to mannitol and citric acid. BE was demonstrated in a 2×2×2 crossover study in healthy subjects1 (204 completers) with pre-specified limits of 90.00–111.11% for AUC and Cmax according to the EMA’s GL (NTID). Both the new and old formulations were administered as a single 600 µg dose (3×200 µg). PK-metrics were adjusted for the baseline.
PE of AUC0–72 was 99.3% (90% CI: 95.6–103.2%) and of Cmax 101.7% (98.8–104.6%), both easily fulfilling the requirements for BE. Post-hoc power was >99%.

However, within three months of the new formulation’s release to the French market, AEs skyrocketed (dizziness, cramps, headaches, and hair loss). Within 24 days the ANSM received 9,000 (!) AE-reports. The French Minister of Health adressed these patients concerns on September 15th by asking Merck to reintroduce the previous formulation within 15 days, on a temporary basis and under medical prescription only for patients with persistent and undesirable side effect.2,3 An analysis of 5,062 patient complaints by the ANSM concluded that while ‘thyroid imbalances can occur for some patients during the transition’ between the old and new formulations, the reported symptoms ‘are in line with those experienced with the previous formulation. No new type of adverse event related to the new formulation was found’.4

Now what?


  1. Gottwald-Hostalek U, Uhl W, Wolna P, Kahaly GJ. New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials. Curr Med Res Opin. 2017;33(2):169–74. doi:10.1080/03007995.2016.1246434.
  2. Macdonald G. French police visit Merck KGaA Lyon plant as part of levothyrox probe.
    in-Pharma Technologist. 05-Oct 2017. online.
  3. Melville NA. Side Effects Skyrocket in France With Levothyroxine Reformulation. Medscape. October 11, 2017. online.
  4. ANSM. Point d’actualité sur le Levothyrox et les autres médicaments à base de lévothyroxine – Communiqué. 11/10/2017. online.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
ElMaestro
Hero

Denmark,
2017-11-26 14:46

@ Helmut
Posting: # 18008
Views: 487
 

 Levothyroxine: A black swan?

Hi Hötzi,

» Now what?

Now I believe you will se an agency put exactly that information into the public domain which largely acquits the agency itself, by modest but carefully deliberated press releases or comments to news media. Along with attempts from the Sponsor's side to control the volume and nature of information I am sure, I am really, really 120 million % convinced, that the need to steer the public opinion in a specific direction will trump objective science.
This isn't BE anymore but is now a communications exercise. I am afraid that an objective root cause investigation is wishful thinking.

I could be wrong, but…


Best regards,
ElMaestro

A potentially biased estimator may be a relevant estimator. The case of REML speaks volumes.
nobody
Senior

2017-11-26 16:51

@ Helmut
Posting: # 18009
Views: 470
 

 Levothyroxine: A black swan?

L-Thyroxine (as an endogenous aminoacid with strong hormonal effects) is somefing very special, as recognized long ago, e.g.:

https://www.aace.com/files/position-statements/levothyroxine.pdf

https://www.endocrine.org/~/media/endosociety/files/advocacy-and-outreach/position-statements/all/lt4positionstatementwithmembercommentsheader.pdf?la=en

http://online.liebertpub.com/doi/pdf/10.1089/105072504773297867

or James V. Hennessey, Generic vs Name Brand L-Thyroxine Products:
Interchangeable or Still Not? J Clin Endocrinol Metab, February 2013, 98(2):511–514

Some people have to make the same experience made in the past again and again...

Kindest regards, nobody
Helmut
Hero
Homepage
Vienna, Austria,
2017-11-26 17:37

@ nobody
Posting: # 18010
Views: 462
 

 Were physicians/patients aware of the change in the formulation?

Hi nobody,

» L-Thyroxine (as an endogenous aminoacid with strong hormonal effects) is somefing very special, as recognized long ago, e.g.: […]

Sure. Dose finding for levothyroxine is a pain in the ass (NTID, long half life, large between-subject variability). Hence, most endocrinologists would not switch their patients from one product to another one.
Note that the FDA’s guidance is even less stringent than the EMA’s. In the study of Gottwald-Hostalek et al. the CVintra of Cmax was 17.7%. According to the FDA’s RSABE (assuming CVwT=CVwR) that would translate into implied BE-limits of 83.11–120.33%…
I think that neither physicians nor patients were aware of what was going on – that wasn’t a product-switch but a change in the formulation. Both thought to take still the same product of the same manufacturer.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2017-11-26 18:00

@ Helmut
Posting: # 18011
Views: 453
 

 Were physicians/patients aware of the change in the formulation?

» I think that neither physicians nor patients were aware of what was going on – that wasn’t a product-switch but a change in the formulation. Both thought to take still the same product of the same manufacturer.

Reformulation -> new product. End of story ;-) Endocrinologists don't support any switching. This was a switch without prior info to patients/docs. Failed. Expectable. For this compound. This has never been discussed broadly by the authorities (read stories of proposed scientific meeting on this topic, which never took place). Too much politics. As Mr. Denmark pointed out. :-)

Kindest regards, nobody
ElMaestro
Hero

Denmark,
2017-11-26 18:30

@ Helmut
Posting: # 18012
Views: 456
 

 Were physicians/patients aware of the change in the formulation?

Hi Hötzi,

» Hence, most endocrinologists would not switch their patients from one product to another one.

What planet are you from?:-D:-D:-D Endocrinologists, pardon me, likely have no idea. Besides, in many countries they have little (not zero, but just little) control over which drug (brand or generic) is given at the pharmacy.

I could be wrong, but…


Best regards,
ElMaestro

A potentially biased estimator may be a relevant estimator. The case of REML speaks volumes.
DavidManteigas
Regular

Portugal,
2017-11-27 17:53

@ Helmut
Posting: # 18014
Views: 355
 

 Levothyroxine: A black swan?

There isn't any biological background that might explain this issue? Or problems during manufacturing? This is really awkward... the CI and point estimate are far more "perfect" than I am used to see. In fact, in full replicate studies, I've seen reference drugs "performing" poorly when compared with single administrations of themselves... Is the dose-toxicity so sensible for this drug that event the narrower limits does not apply in this case? Did a quick search and haven't find any study reporting the dose-response of this drug
Helmut
Hero
Homepage
Vienna, Austria,
2017-11-27 20:35

@ DavidManteigas
Posting: # 18015
Views: 312
 

 Levothyroxine: A black swan?

Hi David,

» There isn't any biological background that might explain this issue? Or problems during manufacturing?

No idea.

» This is really awkward... the CI and point estimate are far more "perfect" than I am used to see.

For this drug, not. The relative BA (against a solution) is ~100% and the variability low to moderate. Check out the NDAs and ANDAs at FDA’s site. You will find a lot of studies with similarly narrow CIs (even with much smaller sample sizes).

» In fact, in full replicate studies, I've seen reference drugs "performing" poorly when compared with single administrations of themselves...

Normal for HVD(P)s.

» Is the dose-toxicity so sensible for this drug that event the narrower limits does not apply in this case?

No idea.

» Did a quick search and haven't find any study reporting the dose-response of this drug

The FDA’s guidance gives this explanation:

FDA has concluded that levothyroxine sodium is a narrow therapeutic index (NTI) drug based on the following evidence:

  • The range between serum levothyroxine therapeutic and toxic concentrations is narrow;
  • Some levothyroxine-associated toxicities are serious and/or irreversible;
  • Sub-therapeutic levothyroxine concentrations result in inadequate treatment and lead to poor clinical outcomes;
  • Levothyroxine sodium requires individual dose titration to achieve a satisfactory balance between maximizing efficacy and minimizing serious dose-related toxicity;
  • Therapeutic drug monitoring based on serum TSH and total or free-T4 levels is routinely employed to facilitate levothyroxine dose titration; and
  • Levothyroxine has small-to-medium within-subject variability.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
nobody
Senior

2017-11-28 08:53

@ DavidManteigas
Posting: # 18016
Views: 285
 

 Levothyroxine: A black swan?

...don't bother to follow the links I posted above (as a starter). They are totally irrelevant, as usual... :-)

Kindest regards, nobody
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