The paper below seems to be being quoted as support for once weekly dosing with levothyroxine.
The Effect of Daily versus Weekly Levothyroxine Replacement on Thyroid Function Test in Hypothyroid Patients at a Tertiary Care Centre in Haryana
Rajesh Rajput* and Vaibhav Pathak
ncbi.nlm.nih.gov/pmc/articl...
I am very much NOT convinced. The following explains at least some of the reasons I think it is unacceptable as support for once weekly dosing. It certainly does not adhere to the full claims of evidence based medicine, and does not, in my view, constitute even a properly conducted trial.
The trial was performed on only 100 patients.
Far too small a cohort.
Other than being hypothyroid, taking levothyroxine and not being pregnant, post-partum or having a co-morbid disease, there is no consideration of other possibly important issues. Such as some of the cohort being athyreotic, or B12 deficient, or iron deficient, or their gender.
The trial period was twelve weeks – two six-week periods.
Given that six weeks is often quoted as the time required for blood test results to stabilise after even a small change in dose, what evidence is there that six weeks is adequate after a gross change?
The TSH reported was 2.8 (daily) and 3.9 (weekly). In the opinions of many, both of those are too high.
The conclusion claims it is reasonable “especially for those who have issues with compliance”. But there is nothing about change in compliance in the rest of the abstract. And, if compliance did change in the trial, or does change in real world use of once weekly dosing, that is an extremely important factor.
“When higher-than-usual doses are needed to maintain TSH in the normal range, clinicians need to find out the reason behind it.”
Whilst I agree that it would be desirable for patients and doctors to know why, does it make any real difference if you need 2, or 2.5 or 3 micrograms of levothyroxine per kilogram? Even in cases where the reason is known (e.g. gastroparesis), what is to be done is the more important question.
“One of the most common reasons for poor response to therapy is non-compliance. Non-compliance in hypothyroid patients is due to the need to take the drug daily on an empty stomach. After taking the drug, patients have to wait at least 30 min until they can have a meal, including tea or coffee, to ensure proper absorption of the drug. The need to take the medication on a daily basis in the fasting state, to avoid other medications hampering absorption for the next 3–4 h, interferes with the daily routine of the patient and will result in poor compliance which causes poor disease control.”
Conflates issues of absorption, interference from food and drink, with issues of compliance.
The paper reports that twice-weekly, alternate-day and weekly therapy have all been tried. But completely ignores another potentially viable approach, bed-time dosing.
“Since the elimination half-life of LT4 is about 7 days, and its biological effect may last longer, giving it once weekly seems a logical alternative.”
This completely misunderstands the situation. If you take, say, paracetamol (half-life sometimes said to be 4 hours), the blood level rises from nothing to a peak very quickly, then to half that peak in four hours.
But with levothyroxine, there is already a significant amount of T4 present in a healthy or properly-dosed person. Much of which is bound. So the effect of a large extra dose of levothyroxine is very different. First, FT4 will rise, possibly dramatically. Then TT4 will rise, but only as far as it can given the amount of binding protein available. In time, they will drop - not to the start point (with paracetamol it was, of course, zero), but to less than the start point. Effectively negative.
“Also, LT4 is a prohormone which is converted in the body tissues into metabolically active TT3 by the local deiodinase enzyme.”
No, LT4 is NOT converted into TT3. It is converted into T3 – some of which might then, possibly, get released back into the bloodstream and get bound as TT3.
I suspect that the very important T4 to T3 conversion by the thyroid itself has simply been ignored. It isn’t mentioned.
“Also, weekly dosing may not only improve compliance in patients but could also be advantageous to nurses or other caregivers taking care of patients who are unable to dose themselves.”
The ethics of promoting advantages to anyone other than the patient are questionable. (I’d accept the possibility that making something easier to dose properly might result in a benefit to a patient but that is not what is claimed.)
“At baseline (day 0), patients in group I were advised to continue with their daily LT4, while patients in group II were given 7 times the daily dose once every week.”
Changing to a weekly dose in patients who are claimed to be euthyroid on stable doses could be dramatically different to what happens to patients who have been non-compliant (or for any other reason are low in thyroid hormones).
There is no evidence that a 7 times dose will be absorbed to even a similar percentage as daily doses.
“Table 1. Baseline characteristics of study groups I and II”
These tests use Total T4 and Total T4.
“A total of 5 patients (3 in group I and 2 in group II) were lost to follow-up.”
That is 5% of the sample. Of course, losses to follow up are common, but if they were lost because they were unhappy with the regime, that would make a huge difference to the possible conclusions.
The end of 6 and end of 12 week tests give absolutely no information about what the biochemical state was on any of the other 82 days covered by the test period.
With daily dosing the highest level of T3 is usually observed about two days after a dose of T4, there could be a massive overdose of T3 at that point or somewhere in the periods between tests. Assuming local conversion entirely compensates would be equivalent to claiming that an overdose of T4 is impossible.
“The weekly administration of T4 may cause hyperthyroidism-like symptoms and signs during the initial few days of therapy and in the long term can have a detrimental effect on the heart, muscles, and bone. In the present study, we assessed the patients clinically for signs and symptoms of hyperthyroidism using the HSS score and found that it was not suggestive of hyperthyroidism during the entire study period in both groups. However, we did not assess 24-h electrocardiogram monitoring, echocardiography, as well as bone and muscle parameter measurements which need to be assessed in future studies. The available literature suggests that weekly LT4 is safe from a cardiac point of view; however, due to the small number of patients and short follow-up in those studies, firm safety data for weekly therapy have not been established.”
In other words, we didn’t check, and we don’t know. It might or might not be safe. Which, in my opinion, undermines this study as supporting any future treatment by weekly dosing.
From my own point of view, we should consider what happens in a healthy person. Thyroid hormone is released in tiny pulses under the control of an extremely complicated mechanism. Daily levothyroxine dosing is already too far away from that state. I would very much like to see research into near-continuous dosing. Not moving treatment dramatically further away from the healthy state.
Added:
Don't be shy about pointing out any mistakes I have made, or issues I have missed. Without a doubt, more eyes see more. 
Levothyroxine dosage and the limitations of current bioequivalence standards
