Thyroid UK

When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients

Before going any further, this research was sponsored IBSA - who are behind the Tirosint product.

There are many here who would agree that there appear to be differences between makes of levothyroxine. If we accept that the products contain the same amount of levothyroxine, we do need another explanation as to why.

The paper suggests stomach acidity. I am not convinced. I suspect it is the alkalinity in the intestine. After all, levothyroxine is more soluble in alkaline than acidic or neutral water solutions. But if the maximum alkalinity is dependent on how acidic the stomach is, then the two could very well go hand in glove with each other.

Also, could the amount of levothyroxine that is not absorbed be one of the causes of problems lower down the intestinal tract? That is, if we absorbed 100% of the levothyroxine, we'd not have gut issues. Many seem to absorb about 80% and have some gut issues. Perhaps those who only absorb 60 to 70% have the worst gut issues? (Only trying to think through why a well-absorbed gel cap would actually be different to an indifferently or poorly absorbed tablet.)

J Pharm Pharm Sci. 2015;18(5):844-55.

When Bioequivalence in Healthy Volunteers May not Translate to Bioequivalence in Patients: Differential Effects of Increased Gastric pH on the Pharmacokinetics of Levothyroxine Capsules and Tablets.

Seng Yue C1, Benvenga S, Scarsi C, Loprete L, Ducharme MP.

Author information

1 Learn and Confirm Inc., St-Laurent, Quebec, Canada...



Clinical studies have suggested that proton pump inhibitors may decrease levothyroxine absorption and an in vitro study suggested that the effect of pH on dissolution may differ with formulation. To determine the impact of formulation on the pharmacokinetics of levothyroxine in altered gastric pH conditions, this study compared the pharmacokinetics of levothyroxine capsules and tablets, two formulations deemed bioequivalent in healthy volunteers under fasting conditions, when taken with or without esomeprazole.


Two clinical studies were conducted in healthy volunteers given single dose levothyroxine (600 mg) with a 45-day washout period. In Study 1 (parallel-design/two-way crossover), 16 subjects received either levothyroxine capsules or tablets, each group with or without prior administration of intravenous esomeprazole (maximum dose of 80 mg). In Study 2 (two-way crossover), 16 subjects received both capsules or tablets after intravenous esomeprazole. Blood samples were collected pre-dose and up to 24 hours post-dose. Baseline-adjusted pharmacokinetic parameters were calculated: Cmax (maximal concentration), Tmax (time to Cmax), AUC0-t (area under the concentration-time curve from 0 to the last detectable concentration), AUC0-6 and AUC0-12 (areas under the curve from 0 to 6 and 12 hours, respectively). Analyses of variance were conducted to compare ln-transformed Cmax and AUC. Non-parametric Tmax analyses were done.


In Study 1, esomeprazole caused a greater decrease in overall levothyroxine exposure of tablets vs. capsules (13% vs 6% for Cmax, 18% vs. 14% for AUC(0-6), 17% vs. 5% for AUC(0-12) and 10% vs. 8% for AUC(0-t)). In Study 2 esomeprazole administration resulted in a 16% smaller levothyroxine exposure with tablets vs. capsules. No statistically significant differences in Tmax were found.


Although both formulations are considered "bioequivalent" in healthy volunteers, they may not necessarily be bioequivalent in patients with impaired gastric pH conditions. Levothyroxine capsules may therefore be more appropriate for patients with decreased gastric acidity.

PMID: 26670370

Free full text available here:


Strongly urge you to download the PDF rather than trying to use their PDF reader embedded on the page!

Updated 8th July 2017: The paper contains an obvious typo - that I had missed. It says (600 mg) where it should be (600 mcg) or, preferably (600 micrograms). Is it somewhat concerning that the experts can't get it right.

11 Replies

Well, there's a surprise! :)


Aren't they just saying that people with low stomach acid will absorb more from a capsule than a solid tablet?



It is good, though, to have it in print. Further, it does help to undermine the standard bioequivalence testing. That is, take some healthy volunteers, give them 600 micrograms of levothyroxine and measure FT4. Wait a few weeks, do same again with another tablet (or a placebo) and check the differences. Testing like that allows for absolutely no possibility such as is described - low stomach acid reduces absorption. Nor does it allow that any other factor whatsoever else might confound that testing in those who actually need to take levothyroxine.

It also supports what has been said here from almost the very first post - Proton Pump Inhibitors (PPI) absolutely WILL affect absorption. (Even here, this trial quite properly delivered the PPI by injection. That would remove any direct interaction between a PPI tablet and the levothyroxine which could occur in the stomach of those on oral PPIs.)


I do not like 'clinical trials' the outcomes are decided before the trials and any adxerse reactions ignored.

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You say that as if I had actually asked you to like it, or any other paper reporting a trial.

Whether you like them, believe them, read them, or not, does not unpublish them. By having been published, they become part of the milieu of understanding (or misunderstanding). Knowing what has been published might well be to our advantage.


Glynisrose but surely without clinical trials there would have been no treatment for hypothyroidism aka Murray and Horsely plus I think some very unfortunate greyhounds who died for us. They may not be ideal but they have moved things forward from a death sentence to a treatable illness.


With clinical trials where the results aren't liked by the producer of the drug who is sponsoring the trial then they bury the data if they think they can still get the drug approved.

It's only when loads of patients report side effects particularly using something like the yellow card system are the adverse results published in places like prescribing guidelines and on patient information leaflets.

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Very interesting paper. It makes me think of something I read somewhere about how the half-life of thyroid replacement will increase if you're hypothyroid, as your whole body is slowed. But maybe that was somewhere like Stop the Thyroid Madness.

Also suggests that as you get better, and digestion improves, patients might actually need a decrease. But that if the decrease is too great, everything comes crashing down again, which sounds quite a familiar story.

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I think it is contrariwise!

In someone who is hypothyroid, the half-life of levothyroxine is reduced because they use it up as soon as they can. In hyperthyroid people, levothyroxine can hang around for longer because it is not needed. (Everything is simplified - this too.)


Thanks Helvella, interesting!

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Another obvious issue is that the operation of the intestines is Thryoid dependant. The ion chanels there depend upon both Mitchonondrial activity an its stimulation by T3. Before T3 I had low levels of multiple nutrients, all of which have become normal or high following T3 administration. This is likely to mean that Hypothyroid patients malabsorb T3 along with other proteins. I had low Tryosine, low Tryptophan, only average B12 despite high supplementaiton, low B9 all despite supplementation, low Vitamin D despite high supplementation. I had to discontinue all these supplements on T3.


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