Pregnancy and the imods

P

There are 4 approved drugs that bind to the sphingosine-1-phosphate (S1P) receptor fingolimod is one another is siponimod and then there is ozanimod and recently ponesimod…What’s the difference?

The receptor mediating the main effect on active MS is S1PR1

They all bind to this target and a few others. fingolimod hits S1P1,3,4,5, ponesimod is suggested to be S1P1-selective but it binds to others too (the lower the number the stronger the binding. This is the concentration needed to induce half maximal response. .

But important differences are how long they hang around for and this depends what happens when the drug is broken down.

Fingolimod has to have a phosphate group added to become active and this has a long half-live meaning it takes 6-9 days for half of the drug to disappear so in 12-18 days you have a quarter or for our American readers one fourth and an eight in 18-27 days. To contrast this with a monoclonal antibody where the half-life is about 1month and because you give a did dose to start it is still at high enough levels to inhibit B cells lasting months. With fingolimod it blocks repopulation for about 1month so that is about 3-4 half-lives. The way that fingolimodworks is largley because it traps cells in the lymph glands so they cant get into the blood so they cant get into the brain and without that lesion formation is blocked. So once cells come back in the blood if you stop treatment then disease can come back to cause a relapse, but it can be the relapse from Hell because the disease causing cells have a break on them, take it away and they come back at once and this can be called a rebound.

Barry et al said the timing of severe relapses after stopping fingolimod appears somewhat predictable, with events occurring approximately within 2–4 months after stopping fingolimod. A review of the initial case reports noted that the relapses occurred between 4 and 16 weeks after stopping fingolimod. A separate review of cases with tumefactive lesions ranged in onset from 3 to 18 weeks after fingolimod cessation.

So if you are on fingolimod and want to have a baby and you are female and you stop fingolimod there is a risk of rebound/relapse in the study below about 60% of people had a relapse. However what will be the case with the other drugs.?

It could be much quicker woth ponesimod as the half live is a day and a half and cells can repopulate within a week, This is good if here is an adverse effect, and you want to stop, but it is possible that disease comes back. How quickly?

I would like to know it could be quick, meaning if you stop treatment you will suffer the consequences or you /your neuro needs a plan on how to switch to something else. On first look the half life of ozanimod is short and so disease reactivation could be very quick, but it is broken down to a molecule that is also active and one has a long half-life and so it takes time for white cells to return.

So as I have said when every you start a compounds you should also consider what you aim to do in the future and if having a family is the plan make sure you discuss this with your neuro/MS

Disease reactivation after fingolimod cessation in Multiple Sclerosis patients with pregnancy desire: A retrospective study. .Mult Scler Relat Disord. 2022 Jul 22;66:104066. doi: 10.1016/j.msard.2022.104066. 

Reactivation of Multiple Sclerosis (MS) activity has been described after fingolimod cessation. Because of its contra indication during pregnancy, switch towards lower efficacy treatments are frequent in MS patients with childbearing desire but expose them to a risk of disease reactivation. In this retrospective study including 44 women with MS, a significant increase of the median annualized relapse rate was found in the year following fingolimod discontinuation compared to the period before (p < 0.0001), and 57% of women experienced at least one relapse. When considering to start fingolimod, particular attention should be paid to women with a short-term pregnancy desire.

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MouseDoctor

4 comments

  • Prof G once advised of the following protocol when swooping from Fingolimod to Cladribine –
    “ in our center ,Blizard Institute, Barts and The London School of Medicine and Dentistry, we measure the lymphocyte counts weekly, and when they get above 800 per uL, we dose the patient with cladribine. The reason we don’t want to wait until they get above 1000/uL, which is on the label, is because you go into that period where you get rebound. “

    Could this approach be also applied if swopping from Fingolimod to another DMT ?

    • Yes it makes sense you also want to think how quickly the drugs take effect with anti CD20 it is pretty quick within 1 month

  • may I suggest to correct the many typing errors in this text including in the header to table 1 (“cities”??)?. they make it difficult to follow the text. Thank you!

    • You may suggest….but it is probably not going to happen…there is no support, Being dyslexic and a rubbish speller it doesn’t help as I often dont see them, but I am sure we can put the specific cities (Specificities) down to microsoft trying to be intelligent and failing as it seems to be a Word thing.autocorrecting. We have dicussed an editor but these things have costs and rather than an editor, it would be better to have another contributor.

      As I have a dayjob, the blog is often a night job and 1-3am in the morning, i forget to re-read the post before it goes live. I used to wait and then correct it once it was live and easier to read on my big screen rather than laptop, however I am told once it is posted it is out there and gets emailed so many people dont see the changed text anyway. I should re-read first….sorry.

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